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Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428-435
Abstract
Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
... Diseases are conditions in which cells fail to maintain homeostasis due to molecular or structural alterations and damage caused by physical and chemical stimuli [2,15]. Various stimuli can damage cells and activate inflammatory pathways, which have four components: inducers, sensors, mediators, and target tissues ( Fig. 1) [2,[16][17][18][19]. Inducers stimulate the sensory receptors of immune cells, induce the secretion of inflammatory mediators (IMs), and may be classified as microbial or non-microbial [19]. ...
... Various stimuli can damage cells and activate inflammatory pathways, which have four components: inducers, sensors, mediators, and target tissues ( Fig. 1) [2,[16][17][18][19]. Inducers stimulate the sensory receptors of immune cells, induce the secretion of inflammatory mediators (IMs), and may be classified as microbial or non-microbial [19]. Non-microbial inducers may be further classified as exogenous substances of inducers (Exo-SIs), which are introduced into the body from an external source, or endogenous substances of inducers (Endo-SIs), which are generated inside the body. ...
... These internal systems protect the human body from stressors, Exo-SIs, and Endo-SIs. However, inappropriate, excessive, or prolonged activation of these systems can damage the human body [2][3][4][5][6]11,12,17,19,[107][108][109]. ...
In Harrison’s Principles of Internal Medicine, human understanding is emphasized as one of three necessary characteristics that a physician must have. Inflammation, which is caused by inflammatory inducers (inf-ids), is a fundamental feature of disease at the cellular and molecular levels. Inflammation protects the body, but excessive or prolonged inflammation can be damaging and can cause disease. Humans are repeatedly exposed to external and internal environmental factors that generate inf-ids throughout their lives. External environmental factors include microbial and non-microbial inf-ids, as well as stressors that inevitably arise during social interactions. Internal environmental factors include the adaptive physiological response that is present from birth. Inf-ids may also be produced by the four-step habit loop, which consists of a cue (e.g., stressor), emotions, routine act (adaptive response), and a reward. Immune cells in the circulatory system and in tissues may have positive and negative effects in inflammatory responses. However, low-grade inflammation may be difficult to detect. We propose a model of disease development that integrates external and internal environmental factors from the perspective of human understanding.
... Inflammation is a protective mechanism against infection or tissue injury. During the course of inflammation, immune cells, such as neutrophils and monocytes, are recruited in several phases and stimulate the formation and release of different cytokines, chemokines, growth factors, and lipid mediators [1][2][3]. In the inflammatory process, monocytes differentiate into macrophages, which have three main tasks: the production of immunomodulators, phagocytosis, and antigen presentation [4,5]. ...
... Following subsequent incubations with 200 mM dithiothre-itol (in 50 mM NH 4 HCO 3 ), 200 mM iodoacetamide (in 50 mM NH 4 HCO 3 ), and again 200 mM dithiothreitol, the proteins were digested overnight (15 h) using 100 µg/mL trypsin in 50 mM acetic acid (trypsin-to-protein ratio of 1:50). The reaction was stopped by acidification with concentrated acetic acid (pH [3][4]. Following the addition of internal standards (heavy labeled peptides with sequences corresponding to each analyte peptide), the samples were extracted using Strata-X SPE 33 µm Polymeric Reversed Phase cartridges (100 mg/3 mL, Phenomenex LTD, Aschaffenburg, Germany). ...
The understanding of the role of LXR in the regulation of macrophages during inflammation is emerging. Here, we show that LXR agonist T09 specifically increases 15-LOX abundance in primary human M2 macrophages. In time- and dose-dependent incubations with T09, an increase of 3-fold for ALOX15 and up to 15-fold for 15-LOX-derived oxylipins was observed. In addition, LXR activation has no or moderate effects on the abundance of macrophage marker proteins such as TLR2, TLR4, PPARγ, and IL-1RII, as well as surface markers (CD14, CD86, and CD163). Stimulation of M2-like macrophages with FXR and RXR agonists leads to moderate ALOX15 induction, probably due to side activity on LXR. Finally, desmosterol, 24(S),25-Ep cholesterol and 22(R)-OH cholesterol were identified as potent endogenous LXR ligands leading to an ALOX15 induction. LXR-mediated ALOX15 regulation is a new link between the two lipid mediator classes sterols, and oxylipins, possibly being an important tool in inflammatory regulation through anti-inflammatory oxylipins.
... Prior to the definitive identification of these microbial pattern recognition receptors, these receptors were characterized as transmembrane proteins that activated the NF-kB signaling pathway [6]. Medzhitov and Janeway, discovered that this yet to be identified candidate receptor contained Leucine-Rich Repeat (LLR) domain. ...
... Parainflammation is an adaptive response that corresponds to the degree of tissue malfunction. In basal state the tissue resident macrophages response is muted and takes on a maintenance role [6]. Under noxious and stressful tissue environments the response borders on overt inflammation. ...
... The etiology of periodontitis is significantly influenced by the damaging nature of ROS. [10,11] Treatment with medications that prevent the creation of free radicals or counteract their effects may be beneficial therapeutically since free radical generation seems to be crucial for the prevention of tissue deterioration. Antioxidant therapy has been proposed by numerous studies as a potential periodontal disease treatment strategy. ...
... [4,7] For individuals with chronic gingivitis, Chandra RV et al. [18] . and Singh et al. (2022) [16] examined the effects of systemically prescribing lycopene as a monotherapy and as an alternative to SRP. [10,14] In a study by Singh S et al., 2022 [16] , when the risk of bias was analyzed, a substantial risk of bias was found. [16] Solid lipid microparticles containing lycopene were created by Tawfik et al. in 2019 [5] and their biochemical and clinical effects on the treatment of chronic periodontitis were evaluated. ...
Background: Lycopene is a dietary antioxidant which provides defense against oxidation. Oxidative stress may result in periodontal tissue damage. There is a positive relationship between lycopene consumption and reduction in the risk of development of degenerative diseases caused by free radicals, such as periodontitis and other diseases like cancer, cardiovascular diseases, asthma, arthritis, stroke, hepatitis. This systematic review discusses the studies conducted to assess the effect of lycopene in periodontal health. Aim: To evaluate the effect of lycopene in maintaining periodontal health. Search Methods: An electronic database search was conducted from the following databases: PubMed, EBSCO Host, Science Direct, EMBASE and Google scholar. Selection Criteria: Randomized controlled trials, experimental studies, case-control studies, and cohort studies published in peer reviewed journals in English language were included. Case reports, case series, animal model studies, in-vitro studies, studies where lycopene was combined with other antioxidants or with additional therapeutic methods and unpublished research were excluded. Data Collection and Analysis: Total 36451 results were obtained after database search. It included case- control studies, experimental studies, reviews and randomized control trials. Out of which, only six studies satisfied the selection criteria. Data extraction sheet was prepared & the studies were analyzed. Results: Out of the six studies analyzed, all were randomized controlled trial. Conclusion: Lycopene has been used widely as an antioxidant in the treatment of chronic diseases. However, Literature is deficient in the studies regarding the effect of lycopene on periodontal health.
... Although appropriate inflammatory responses maintain homeostasis, their dysregulation can lead to social impairment and the development of chronic diseases. Further, although inflammation [6] is influenced by environmental factors and genetic background [7], the relationship between dietary factors, such as nutrients, foods, and dietary pa erns, and the inflammatory response remains unclear. ...
The aim of this study was to investigate the effect of a senior-friendly diet based on the dietary inflammatory index (DII) on the nutritional status and health indicators of older people. A total of 256 participants were classified into tertiles based on their DII values and split into intervention (n = 201) and control (n = 55) groups. The intervention group was provided with a senior-friendly diet, and the control group was allowed to eat their usual diet. Before and after the trial, anthropometric measurements, blood analyses, and questionnaires were completed for both groups. The mean age of the participants was 82.49 years, and 66.4% were female. On average, participants had 2.5 medical conditions, with a notable prevalence of cardiovascular disease. Following the intervention, the energy, carbohydrate, protein, and fat intakes significantly increased in the intervention group compared to pre-intervention levels. Tertile 3 exhibited substantial improvements in total nutrition score, NQ-E balance, and DII total score, as well as in triglycerides and blood glucose, attributed to this dietary intervention compared to other groups. In comparison with Tertile 1, nutrient intake and nutritional status in Tertile 3 were closely associated with significant influencing factors of the dietary intervention. For the group with the worst DII (Tertile 3), this dietary intervention greatly improved nutritional status, nutrient intake, and clinical indicators; thus, this senior-friendly diet appears to be beneficial for elderly people with nutritional vulnerabilities.
... Inflammation, a palliate response of the body to various offenses, is a double-edged sword. While it is typically recognized as a process for the remission of diseases, this process's persistence may lead to various diseases associated with chronic inflammation, [1,2] including arthritis, atherosclerosis, neuropathic pain and even cancer. [3][4][5] Steroids are potent anti-inflammatory agents and have a wide range of adverse effects that increase blood sugar levels, retain fluid, impairs wound healing, increases appetite, and produces heart burn, irritability, and osteoporosis. ...
Sinapic acid (SA) is a potent nutraceutical or natural bioactive compound which is commonly present in the human diet. It was evaluated for its anti-inflammatory activity by in- vitro methods like albumin denaturation assay, heat induced and hypotonicity induced haemolysis, Cycloxygenase-2 (COX-2) and lipoxygenase (5-LOX) inhibition assay at different concentrations. Aspirin (200 μg/ml) and Indomethacin (100 μg/ml) were used as standard drugs. The results showed that Sinapic acid at a concentration range of 10-500 μg/ml significantly (P<0.001) protected the heat induced protein denaturation. Heat and hypotonicity induced haemolysis of erythrocyte was significantly (P<0.001) inhibited at the concentration of 500 μg/ml. The (COX-2) and (5-LOX) enzymes were significantly (P<0.001) inhibited by Sinapic acid. The results indicate that Sinapic acid may be a potential anti-inflammatory agent.
... Oxidative stress, characterized by an imbalance between free radicals and antioxidants, leads to various inflammatory and cancer-related diseases [7,8]. Inflammation can damage cells, making them prone to infections and chronic diseases, with cytokines such as interleukin 1, β (IL-1β), tumor necrosis factor (TNF-α), and interleukin 6 (IL-6) playing critical roles in its development [9]. In research models, macrophages involved in inflammation release nitric oxide and inflammatory molecules upon LPS stimulation; excessive NO production can lead to cancer metastasis and DNA damage, causing mutagenesis [10,11]. ...
Sorghum is an important cereal with high value as a health food ingredient because it contains various phenolic compounds. Anti-inflammatory activity was assessed using 12 sorghum resources collected from various countries to explore their potential as medicinal resources. The findings revealed that, at extract concentrations of 25 µg/mL and 50 µg/mL, cell survival rates were observed to be between 70 and 80% for most varieties, with the exception of K159081. In the analysis of anti-inflammatory activity, measured by the rate of nitric oxide (NO) production, sorghum varieties K159041 and K159081 exhibited NO production rates of 0.46 ± 0.38% and 2.58 ± 0.20%, respectively, indicating significant anti-inflammatory properties. The investigation into anti-inflammatory effects also included examining the expression of the inducible nitric oxide synthase (iNOS) gene, which is related to the inflammatory response triggered by LPS in macrophages. Varieties K159041, K159048, K159077, K159078, K159081, K159089, and K159096 were analyzed for this purpose. Further, an expression test of the cyclooxygenase 2 (COX-2) gene revealed values less than 0.4 in K159077, K159081, and K159089, suggesting these sorghum lines possess higher anti-inflammatory activity compared to others. Additionally, the expression analysis of tumor necrosis factor alpha (TNF-α), a gene identified as an inflammatory cytokine, showed that the mRNA levels in the lines K159048, K159077, K159078, K159088, K159089, K159093, and K159096 were expressed at lower levels relative to other sorghum resources, categorizing them as having high anti-inflammatory activity. Notably, the K159081 line exhibited the lowest expression level of all genes associated with inflammation, marking it as a valuable medicinal resource with potential development as an anti-inflammatory agent.
... These inflammatory states do not appear to be brought on by the usual sources of inflammation, such as infection or injury, which induces redness, swelling, and pain, including heat characterized by tumors and occasionally rubor [15]. As opposed to being connected to host defense or tissue repair, inflammatory states are tied to tissue malfunction and a loss of homeostatic imbalance of one or several physiological systems [16,17]. Also, saturated fats in meat and full dairy products are connected to the development of inflammation [18]. ...
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects the joints of the human body and is projected to have a prevalence age-standardized rate of 1.5 million new cases worldwide by 2030. Several conventional and non-conventional preventive and therapeutic interventions have been suggested but they have their side effects including nausea, abdominal pain, liver damage, ulcers, heightened blood pressure, coagulation, and bleeding. Interestingly, several food-derived peptides (FDPs) from both plant and animal sources are increasingly gaining a reputation for their potential in the management or therapy of RA with little or no side effects. In this review, the concept of inflammation, its major types (acute and chronic), and RA identified as a chronic type were discussed based on its pathogenesis and pathophysiology. The conventional treatment options for RA were briefly outlined as the backdrop of introducing the FDPs that potentiate therapeutic effects in the management of RA.
... Resistance against infectious challenges requires the activation of immune mechanisms to target and eliminate pathogens, aiming to restore host homeostasis and avoid premature death. To accomplish this, mammalians engage the so-called innate and adaptive immunity mechanisms that work in concert to generate a pro-inflammatory state that is absolutely required to cope with infection (Iwasaki & Medzhitov, 2015;Medzhitov, 2008). The innate immune system represents one of the first defensive barriers against invaders and comprises an array of soluble and cellular factors that immediately recognize pathogen-associated molecular patterns (PAMP) and subsequently mediate pathogen killing (Akira et al., 2001). ...
Aedes aegypti females are natural vectors of important arboviruses such as dengue, zika, and yellow fever. Mosquitoes activate innate immune response signaling pathways upon infection, as a resistance mechanism to fight pathogens and limit their propagation. Despite the beneficial effects of immune activation for insect vectors, phenotypic costs ultimately affect their fitness. However, the underlying mechanisms that mediate these fitness costs remain poorly understood. Given the high energy required to mount a proper immune response, we hypothesized that systemic activation of innate immunity would impair flight muscle mitochondrial function, compromising tissue energy demand and flight activity. Here, we investigated the dynamic effects of activation of innate immunity by intra‐thoracic zymosan injection on A. aegypti flight muscle mitochondrial metabolism. Zymosan injection significantly increased defensin A expression in fat bodies in a time‐dependent manner that compromised flight activity. Although oxidant levels in flight muscle were hardly altered, ATP‐linked respiratory rates driven by mitochondrial pyruvate+proline oxidation were significantly reduced at 24 h upon zymosan injection. Oxidative phosphorylation coupling was preserved regardless of innate immune response activation along 24 h. Importantly, rotenone‐sensitive respiration and complex I‐III activity were specifically reduced 24 h upon zymosan injection. Also, loss of complex I activity compromised ATP‐linked and maximal respiratory rates mediated by mitochondrial proline oxidation. Finally, the magnitude of innate immune response activation negatively correlated with respiratory rates, regardless of the metabolic states. Collectively, we demonstrate that activation of innate immunity is strongly associated with reduced flight muscle complex I activity with direct consequences to mitochondrial proline oxidation and flight activity. Remarkably, our results indicate a trade‐off between dispersal and immunity exists in an insect vector, underscoring the potential consequences of disrupted flight muscle mitochondrial energy metabolism to arbovirus transmission.
... IL-6 has a shorter plasma half-life than CRP, which may be a more consistent marker of chronic inflammation. To avoid confounding by infectious or inflammatory process, we evaluated only individuals without clinically significant inflammation (CRP < 10 mg/L), since the lowgrade inflammatory state differs significantly from the acute inflammation [45]. The higher prevalence of male sex in the older adult group compared to the middle-aged group could be due to the study's selective criteria, which included only participants with complete tests and excluded those with significant inflammation, potentially biasing the gender distribution. ...
Emerging evidence indicates an association between blood pressure and inflammation, yet this relationship remains unclear in older adults, despite the elevated prevalence of hypertension. We investigated the association between blood pressure, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and white blood cell (WBC) count in a cohort of 3571 older adults aged 65 and above, and 587 middle-aged participants (55–59 years old). In women aged 65 and above, the relationship between inflammatory markers and blood pressure was consistent, with hs-CRP and WBC emerging as predictors of high blood pressure. For hs-CRP, the adjusted odds ratio (OR) was 1.5 (95% CI, 1.07 to 2.10, P = 0.02), and for WBC, the adjusted OR was 1.41 (95% CI, 1.02 to 1.94, P = 0.04), comparing the highest to the lowest quartiles. In men, only the WBC count was significantly associated with an increased OR for high BP (adjusted OR 1.49, 95% CI, 1.09 to 2.02, P = 0.01) across quartiles. Across the entire study population, in a fully adjusted model, all inflammatory markers were modestly associated with blood pressure levels, while the effect of being over 65 years was the most significant predictor of high blood pressure (OR 1.84, 95% CI, 1.50 to 2.25, P < 0.001). The link between key inflammation markers and blood pressure in older adults varies by sex and biomarker type and may differ from the relationship observed in younger individuals. These relationships are likely to be affected by factors linked to age.
... Inflammatory responses are crucial for protecting the body against various stressors and maintaining physiological integrity [1][2][3]. Through innate and acquired immunity, these defense mechanisms have evolved to enable humans to adapt to a wide range of inflammatory and infectious agents, preventing potential lethality that would result from a lack of adequate immunological resistance. ...
The immune system's inflammatory response is a crucial defense mechanism against infectious agents. At the onset of the pandemic, researchers primarily focused on the respiratory consequences of coronavirus, while overlooking the virus's impact on other organs, such as the brain. However, it is now apparent that post-covid sequelae can persist, especially in those who suffered severe forms of the disease. These symptoms include memory impairment, excessive fatigue, and mood swings. This study examines the possible link between the brain's inflammatory response and these prevalent sequelae, as well as strategies to improve the quality of life for those affected.
... Numerous molecules known as inflammatory cytokines, such as tumournecrosis factor-α (TNF-α), IL-1, IL-6 and many others, are produced by various cell types, particularly by macrophages and mast cells. These cytokines have several roles in the inflammatory process, including activation of the endothelium and leukocytes, as well as initiation of the acute-phase response [15]. Previous studies have indicated the relationship between telomere/telomerase dysfunction and inflammatory signaling [16]. ...
Optic neuritis (ON) is a condition marked by optic nerve inflammation due to various potential triggers. Research indicates a link between telomeres and inflammation, as studies demonstrate that inflammation can lead to increased telomere shortening. Aim: We aimed to determine the associations of telomere-related telomeric repeat binding factor 1 (TERF1) rs1545827, rs10107605, and telomeric repeat binding factor 2 (TERF2) rs251796 polymorphisms and relative leukocyte telomere length (LTL) with the occurrence of ON. Methods: In this research, a total of 73 individuals diagnosed with optic neuritis (ON) were studied and the control group included 170 individuals without any health issues. The DNA samples were obtained from peripheral blood leukocytes, which were purified using the DNA salting-out technique. Real-time polymerase chain reaction (RT-PCR) assessed single-nucleotide polymorphisms (SNPs) and relative leukocyte telomere lengths (LTL). The data obtained were processed and analyzed using the “IBM SPSS Statistics 29.0” program. Results: Our study revealed the following results: in the male group, TERF2 rs251796 (AA, AG, and TT) statistically significantly differed between the long and short telomere group, with frequencies of 65.7%, 22.9%, and 2.0% in long telomeres, compared to 35.1%, 56.8%, and 8.1% in the short telomere group (p = 0.013). The TERF2 rs251796 CT genotype, compared to CC, under the codominant genetic model, was associated with 4.7-fold decreased odds of telomere shortening (p = 0.005). Meanwhile, CT+TT genotypes, compared to CC under the dominant genetic model, were associated with 3.5-fold decreased odds of telomere shortening (p = 0.011). Also, the CT genotype, compared to CC+TT, under the overdominant genetic model, was associated with 4.4-fold decreased odds of telomere shortening (p = 0.004). Conclusions: The current evidence may suggest a protective role of TERF2 rs251796 in the occurrence of ON in men.
... Developing a model to forecast postoperative complications and identify risk factors is crucial. Growing evidence suggests that the prognosis and progression of bowel obstruction are linked not only to bowel dysfunction but also to systemic inflammatory responses (6)(7)(8). The persistent obstruction leads to digestive tract dilation, intestinal barrier compromise, microbial translocation, and infiltration of inflammatory cells like neutrophils, lymphocytes, platelets, and monocytes, indicative of inflammatory responses in clinical settings (9,10). ...
Background
Postoperative complications in adhesive small bowel obstruction (ASBO) significantly escalate healthcare costs and prolong hospital stays. This study endeavors to construct a nomogram that synergizes computed tomography (CT) body composition data with inflammatory-nutritional markers to forecast postoperative complications in ASBO.
Methods
The study’s internal cohort consisted of 190 ASBO patients recruited from October 2017 to November 2021, subsequently partitioned into training (n = 133) and internal validation (n = 57) groups at a 7:3 ratio. An additional external cohort comprised 52 patients. Body composition assessments were conducted at the third lumbar vertebral level utilizing CT images. Baseline characteristics alongside systemic inflammatory responses were meticulously documented. Through univariable and multivariable regression analyses, risk factors pertinent to postoperative complications were identified, culminating in the creation of a predictive nomogram. The nomogram’s precision was appraised using the concordance index (C-index) and the area under the receiver operating characteristic (ROC) curve.
Results
Postoperative complications were observed in 65 (48.87%), 26 (45.61%), and 22 (42.31%) patients across the three cohorts, respectively. Multivariate analysis revealed that nutrition risk score (NRS), intestinal strangulation, skeletal muscle index (SMI), subcutaneous fat index (SFI), neutrophil-lymphocyte ratio (NLR), and lymphocyte-monocyte ratio (LMR) were independently predictive of postoperative complications. These preoperative indicators were integral to the nomogram’s formulation. The model, amalgamating body composition and inflammatory-nutritional indices, demonstrated superior performance: the internal training set exhibited a 0.878 AUC (95% CI, 0.802–0.954), 0.755 accuracy, and 0.625 sensitivity; the internal validation set displayed a 0.831 AUC (95% CI, 0.675–0.986), 0.818 accuracy, and 0.812 sensitivity. In the external cohort, the model yielded an AUC of 0.886 (95% CI, 0.799–0.974), 0.808 accuracy, and 0.909 sensitivity. Calibration curves affirmed a strong concordance between predicted outcomes and actual events. Decision curve analysis substantiated that the model could confer benefits on patients with ASBO.
Conclusion
A rigorously developed and validated nomogram that incorporates body composition and inflammatory-nutritional indices proves to be a valuable tool for anticipating postoperative complications in ASBO patients, thus facilitating enhanced clinical decision-making.
... It is regarded as an adaptive reaction to any negative impact such as inflammatory processes, necrotic cells, and early causes of cell damage, that threaten the stability of the cellular homeostasis. It is a multi-step process involving macrophages and mediator signals (Lugrin and Rosenblatt-Velin 2014;Medzhitov 2008;Iwasaki and Medzhitov 2015). Pathogen-specific receptor activation triggers transcription factors such as NF-κB, leading to the release of inflammatory mediators, including chemokines and inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). ...
Inflammation is an adaptive response that involves activation, and recruitment of cells of innate and adaptive immune cells for restoring homeostasis. To safeguard the host from the threat of inflammatory agents, microbial invasion, or damage, the immune system activates the transcription factor NF-κB and produces cytokines such as TNF-α, IL- 6, IL-1β, and α. Sirtuin 1 (SIRT1) controls the increased amounts of proinflammatory cytokines, which in turn controls inflammation. Three phytoconstituents resveratrol (RES), pterostilbene (PTE), and curcumin (CUR) which are SIRT1- activators and that have marked anti-inflammatory effects (in-vivo), were chosen for the current study. These compounds were compared for their anti-inflammatory potential by in-silico docking studies for IL-6, TNF-α, NF-κB, and SIRT1 and in-vitro THP-1 cell line studies for IL-6, TNF-α. PTE was found to be more effective than RES and CUR in lowering the concentrations of IL-6 and TNF-α in THP-1 cell line studies, and it also showed a favorable docking profile with cytokines and SIRT1. Thus, PTE appears to be a better choice for further research and development as a drug or functional food supplement with the ability to reduce inflammation in metabolic disorders.
Graphical abstract
Schematic representation of in-silico and in-vitro analysis of Resveratrol, Pterostilbene, and Curcumin
... Inflammation and pain are essential components of the body's immune response to detrimental factors like pathogens, damage, or irritants. These responses manifest through symptoms like discomfort, redness, swelling, heat, and impaired function in the affected region (Medzhitov, 2008). Acute inflammation is shortterm and resolves on its own, but when the inflammatory reaction continues over time, it can evolve into chronic inflammation. ...
Yafon (YF), a formula composed of 14 herbal constituents, has been used in folk Thai herbal medicine to treat various indications, including pain relief, antipyretics, and anti-inflammatory properties. Nevertheless, this formula lacks adequate toxicological and efficacy data. Hence, this study aims to assess the safety and efficacy of YF in animal models. The study on acute oral toxicity was conducted by the Organization for Economic Co-operation and Development (OECD) number 420 guidelines. The results demonstrated that the administration of YF at a high dose of 2000 mg/kg did not result in fatality or exhibit any toxicity. The analgesic effect of YF in mice was investigated using the acetic acid-induced writhing test and the formalin test. The anti-inflammatory activity of YF was assessed in rats using the carrageenan-induced paw edema test. This investigation employed YF doses of 200, 400, and 800 mg/kg/day. The study found that all YF doses reduced writhing in the acetic acid, and YF doses of 400 and 800 mg/kg/day reduced the licking time in the late phase of the formalin test. In addition, all YF doses effectively suppressed paw edema in the carrageenan-induced paw edema test. This study demonstrated that the YF formula showed no acute toxicity and possessed acute anti-inflammatory and analgesic effects by blocking pain signals originating from the peripheral nervous system. These findings provided empirical evidence supporting the use of YF formula as an analgesic and anti-inflammatory agent.
... While the eye resists exuberant inflammation, it is susceptible to parainflammation, a state of low-grade inflammation in response to cellular stress that helps restore and maintain tissue functionality (5)(6)(7). Both immune privilege and parainflammation require the sophisticated regulation of the complement cascade, a central part of innate immunity that can cause severe intraocular inflammation if left unchecked (8). ...
Careful regulation of the complement system is critical for enabling complement proteins to titrate immune defense while also preventing collateral tissue damage from poorly controlled inflammation. In the eye, this balance between complement activity and inhibition is crucial, as a low level of basal complement activity is necessary to support ocular immune privilege, a prerequisite for maintaining vision. Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis. Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). In the last two decades, complement activity has been the focus of intense investigation in AMD pathogenesis, leading to the development of novel therapeutics for the treatment of atrophic AMD. This Review outlines recent advances and challenges, highlighting therapeutic approaches that have advanced to clinical trials, as well as providing a general overview of the complement system in the posterior segment of the eye and selected ocular diseases.
... Within these, inflammatory markers previously associated with COVID-19 severity were among the high-contribution features of the severity factor ( Figure 3D and Supplemental Table 3), including IL6, CXCL10, and CXCL8 (IL8) proteins in serum. Proinflammatory soluble proteins are known to modulate metabolism (48,49), transcription (50,51), and other cellular activities (52)(53)(54). Similarly, our analyses revealed strong associations of proinflammatory soluble proteins with transcriptomic, proteomic, and metabolomic pathways and cellular compositions in blood (Supplemental Figure 4, A and B). ...
BACKGROUND
Patients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.
METHODS
We performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.
RESULTS
Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.
CONCLUSION
Our longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04378777.
FUNDING
NIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).
... Inflammation is also involved in developing various diseases. It is triggered by harmful stimuli and conditions such as infection and tissue damage (Medzhitov 2008). As a proinflammatory cytokine, IL-6 is mainly released by T cells and macrophages. ...
Improvement of indoor air quality is beneficial for human health. However, previous studies have not reached consistent conclusions regarding the effects of indoor air filtration on inflammation and oxidative stress. This study aims to determine the relationship between indoor air filtration and inflammation and oxidative stress biomarkers. We conducted an electronic search that evaluated the association of indoor air filtration with biomarkers of inflammation and oxidative stress in five databases (PubMed, Cochrane Library, EMBASE, Web of Science, and Scopus) from the beginning to April 23, 2023. Outcomes included the following markers: interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), malondialdehyde (MDA), 8-hydroxy-2deoxyguanosine (8-OHdG), and 8-iso-prostaglandinF2α (8-isoPGF2α). We extracted data from the included studies according to the system evaluation and the preferred reporting item for meta-analysis (PRISMA) guidelines and used the Cochrane risk of bias tool to assess bias risk. Our meta-analysis included 15 studies with 678 participants to assess the combined effect size. The meta-analysis demonstrated that indoor air filtration could have a marked reduction in IL-6 (SMD: -0.275, 95% CI: –0.545 to –0.005, p = 0.046) but had no significant effect on other markers of inflammation or oxidative stress. Subgroup analysis results demonstrated a significant reduction in 8-OHdG levels in the subgroup with < 1 day of duration (SMD: –0.916, 95% CI: –1.513 to –0.320; p = 0.003) and using filtrete air filter (SMD: –5.530, 95% CI: –5.962 to –5.099; p < 0.001). Our meta-analysis results depicted that indoor air filtration can significantly reduce levels of inflammation and oxidative stress markers. Considering the adverse effects of air pollution on human health, our study provides powerful evidence for applying indoor air filtration to heavy atmospheric pollution.
... The main controversy is whether acupuncture is beneficial to facial edema in the acute stage of Bell's palsy (28,29). To the best of our knowledge, this clinical trial is the first study planned to analyze the effect of facial edema in patients with Bell's palsy in the acute phase by using facial nerve color Doppler ultrasound. ...
Background
Bell’s palsy is an acute peripheral facial neuropathy, which is one of the most common causes of facial palsy of lower motor neurons. Facial nerve swelling is commonly observed in Bell’s palsy. Acupuncture therapy has been widely used in the treatment of Bell’s palsy. However, whether acupuncture can be effectively used in the acute stage is still controversial. There are no clinical trials conducted previously to evaluate the effect of acupuncture on facial nerve edema in Bell’s palsy patients. The study aims to evaluate the potential efficacy of different acupuncture modalities on Bell’s palsy patients in the acute phase, its effect on facial nerve edema, and to preliminarily explore its possible mechanism.
Methods and analysis
In this randomized, controlled trial, 165 Bell’s palsy patients with unilateral onset within 3 days will be recruited and randomly assigned to either the electroacupuncture group (n = 33), the acupuncture group (n = 33), the sham acupuncture group (n = 33), the blank control group (n = 33), or the acupuncture control group (n = 33) in a 1:1:1:1:1 ratio. The participants will receive 4 weeks of treatment and 8 weeks of follow-up. The five groups of participants will receive the following treatments: A: Electroacupuncture + Medication (prednisone acetate tablets, mecobalamin tablets, and vitamin B1 tablets); B: Acupuncture + Medication; C: Sham Acupuncture + Medication; D: Medication only; and E: Acupuncture only. The primary outcome will be the effectiveness rate of different acupuncture modalities in improving facial nerve function after the intervention period. The secondary outcomes will be the recovery speed, the diameter of the facial nerve, the echo intensity and thickness of facial muscles, blood flow parameters of the facial artery, the serum inflammatory level, safety evaluation, and adverse events. Preliminary exploration of its mechanism of action occurs through inflammation and immune response. The difference between groups will be assessed using repeated measure analysis of covariance (ANCOVA) and trend chi-square.
Discussion
The trial will evaluate the efficacy and facial nerve edema of acupuncture for Bell’s palsy patients in the acute phase and preliminarily explore its possible mechanism. The results thus may provide evidence for clinical application.
Clinical trial registration
https://www.chictr.org.cn/bin/project/edit?pid=133211, identifier ChiCTR2100050815.
... 7 Inflammatory response affects tissue homeostasis, increases blood flow, facilitates immune cell activation and migration, and triggers secretion of cytokines, chemokines, and growth factors. 8,9 Acute inflammation ultimately leads to the elimination of infectious agents, of damaged tissues, clearance of inflammatory cells, and return to homeostasis. 10 Persistent acute inflammation may develop into chronic inflammation, which can cause permanent tissue damage. ...
Physical activity has a positive effect on human health and emotional well-being. However, in both amateur and professional athletes, training poses a risk of acute or chronic injury through repetitive overloading of bones, joints, and muscles. Inflammation can be an adverse effect of intense exercise caused by several factors including oxidative stress. The present narrative review summarizes current knowledge on inflammatory markers induced by physical exercise. Post-exercise recovery may reduce inflammatory responses and is key to effective training and adaptation of muscle tissues to sustained physical exertion.
... The significance of this finding is that it may be essential to alleviate the stress response in pets during transport or environmental changes. Environmental stressors can stimulate cells to produce reactive oxygen species, which disrupt the antioxidant defence system and induce the onset of an inflammatory response (Medzhitov, 2008;Herzog et al., 2014). Liver function (AST and ALT) and kidney function (BUN) indices of beagles were also examined in this study, and the results demonstrated that P. acidilactici GLP06 had no adverse effects on liver and kidney function. ...
There is growing interest in the potential health benefits of probiotics for both humans and animals. The study aimed to investigate the effects of feeding the canine-derived probiotic Pediococcus acidilactici GLP06 to adult beagles by analysing the microbiome and metabolome. Twenty-four healthy adult beagles were randomly assigned to four groups. The CK group received a standard diet, while the three probiotic groups, the LG group (2 × 10⁸ CFU/day/dog), MG group (2 × 10⁹ CFU/day/dog), and HG group (2 × 10¹⁰ CFU/day/dog), received the standard diet supplemented with varying amounts of probiotics. The results show that, compared to the CK group, total antioxidant capacity was significantly increased in the MG and HG groups (p < 0.05), and superoxide dismutase and catalase were significantly increased in the HG group (p < 0.05). Compared to the CK group, malondialdehyde and blood urea nitrogen content were significantly decreased in the MG and HG groups (p < 0.05). Additionally, secretory immunoglobulin A activity was significantly increased in the HG group compared to the CK and LG groups (p < 0.05), and immunoglobulin G activity was significantly increased in the HG group compared to the CK, LG, and MG groups (p < 0.05). In addition, compared with the CK group, the abundance of Faecalitalea and Collinsella increased in the LG group, and the relative abundance of Tyzzerella and Parasutterella increased in the MG group. The α diversity and the relative abundances of beneficial bacteria (Faecalibacterium, Lachnospiraceae_NK4A1316, and Ruminococcaceae_UCG-005) were higher in the HG group than in the CK group. Furthermore, acetic acid content was significantly increased in the HG group compared to the CK, LG, and MG groups (p < 0.05). Butyric acid, isobutyric acid, and the total SCFA content were significantly increased in the HG group compared to the CK group (p < 0.05). Moreover, metabolome analysis revealed 111 upregulated and 171 downregulated metabolites in the HG group. In conclusion, this study presents evidence that supplementing with P. acidilactici GLP06 can have a positive impact on antioxidant activity, immunoproteins, SCFAs, and gut microbiota in adult beagles. These findings highlight the potential of probiotics as a dietary intervention to enhance gut health and overall wellbeing in companion animals.
... Contemporary research has illuminated a profound correlation between inflammatory responses and a spectrum of non-communicable chronic diseases (NCDs). This spectrum encompasses disorders ranging from arthritis, hypertension, metabolic syndrome, type 2 diabetes, cardiovascular diseases, obesity, cancer, and even pathologies related to sleep deprivation (Biondi-Zoccai et al., 2003;Medzhitov, 2008;Straub et al., 2010;Armstrong et al., 2013;López-Otín et al., 2013;Dregan et al., 2014;Besedovsky et al., 2019;Drummond et al., 2019;Schunk et al., 2021;Crea, 2022a;Crea, 2022b). A recurring theme in diseases that elicit inflammatory responses is the disruption of cellular and tissue homeostasis (Hotamisligil, 2006;Colaço and Moita, 2016). ...
Strontium (Sr), a trace element with a long history and a significant presence in the Earth’s crust, plays a critical yet often overlooked role in various biological processes affecting human health. This comprehensive review explores the multifaceted implications of Sr, especially in the context of non-communicable diseases (NCDs) such as cardiovascular diseases, osteoporosis, hypertension, and diabetes mellitus. Sr is predominantly acquired through diet and water and has shown promise as a clinical marker for calcium absorption studies. It contributes to the mitigation of several NCDs by inhibiting oxidative stress, showcasing antioxidant properties, and suppressing inflammatory cytokines. The review delves deep into the mechanisms through which Sr interacts with human physiology, emphasizing its uptake, metabolism, and potential to prevent chronic conditions. Despite its apparent benefits in managing bone fractures, hypertension, and diabetes, current research on Sr’s role in human health is not exhaustive. The review underscores the need for more comprehensive studies to solidify Sr’s beneficial associations and address the gaps in understanding Sr intake and its optimal levels for human health.
... These substances play a role in vasodilation, platelet aggregation, leukocyte chemotaxis, and monocyte adhesion. When activated excessively or persistently, inflammation can damage organs and systems, resulting in decompensation, organ dysfunction, and death [93][94][95][96]. ...
Alzheimer's disease (AD) is a stealthy and progressive neurological disorder that is a leading cause of dementia in the global elderly population, imposing a significant burden on both the elderly and society. Currently, the condition is treated with medications that alleviate symptoms. Nonetheless, these drugs may not consistently produce the desired results and can cause serious side effects. Hence, there is a vigorous pursuit of alternative options to enhance the quality of life for patients. Ginkgo biloba (GB), an herb with historical use in traditional medicine, contains bioactive compounds such as terpenoids (Ginkgolides A, B, and C), polyphenols, organic acids, and flavonoids (quercetin, kaempferol, and isorhamnetin). These compounds are associated with anti-inflammatory, antioxidant, and neuroprotective properties, making them valuable for cognitive health. A systematic search across three databases using specific keywords GB in AD and dementia yielded 1702 documents, leading to the selection of 15 clinical trials for synthesis. In eleven studies, GB extract/EGb 761® was shown to improve cognitive function, neuropsychiatric symptoms, and functional abilities in both dementia types. In four studies, however, there were no significant differences between the GB-treated and placebo groups. Significant improvements were observed in scores obtained from the Mini-Mental State Examination (MMSE), Short Cognitive Performance Test (SKT), and Neuropsychiatric Inventory (NPI). While the majority of synthesized clinical trials show Ginkgo biloba has promising potential in these conditions, more research is needed to determine optimal dosages, effective delivery methods, and appropriate pharmaceutical formulations. Furthermore, a thorough assessment of adverse effects, exploration of long-term use implications, and investigation into potential drug interactions are critical aspects that must be carefully evaluated in future studies.
... Chronic inflammation has been identified as the key contributing factor to the malignant state (1). Inflammation occurs when the organism responds to pathogens or to physical or chemical damage to eliminate the source of the damage and restore homeostasis (2). However, the complex crosstalk between cytokines, chemokines, growth factors and reactive oxygen species (ROS) produced by inflammatory cells and injured parenchymal cells during chronic inflammation may lead to carcinogenesis (3,4), which has been well demonstrated in inflammatory bowel disease-associated colorectal cancer (IBD-CRC). ...
The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.
... Inflammation serves as an adaptive response to harmful stimuli such as infection and tissue damage [90][91][92]. A study found that the AF9 YEATS structure domain has higher binding compatibility on lysine crotonylation and AF9 YEATS junction inflammatory gene response to histone crotonylation. ...
Crotonylation is an importantly conserved post-translational modification, which is completely different from acetylation. In recent years, it has been confirmed that crotonylation occurs on histone and non-histone. Crotonylated Histone primarily affects gene expression through transcriptional regulation, while non-histone Crotonylation mainly regulates protein functions including protein activity, localization, and stability, as well as protein-protein interactions. The change in protein expression and function will affect the physiological process of cells and even cause disease. Reviewing previous studies, this article summarizes the mechanisms of histone and non-histone crotonylation in regulating diseases and cellular physiological processes to explore the possibility of precise regulation of crotonylation sites as potential targets for disease treatment.
... In lammation is a response of the human body against various physiological and pathological processes, aimed at protecting the body against infections [1,2]. There are two types of in lammation: chronic and acute [3]. ...
Inflammation is a natural response of the body to defend itself against potential threats and can be reduced through physical activity, proper nutrition, and the use of herbal medicines, which are medicinal plants. In the study, we aim to examine the anti-inflammatory effects of the volatile and ethanolic fractions of two commonly used medicinal plants, Equisetum arvense, and Baccharis trimera. The essential oils were obtained by hydrodistillation of the fresh leaves of the plants, while the ethanolic extracts were obtained using classical methodologies. All fractions were tested for anti-inflammatory activity, evaluating their ability to stabilize the red blood cell membrane and inhibit the spreading, and phagocytosis by macrophages, at concentrations varying from 200 to 600 µg mL-1. The results of the experiments suggest that the ethanolic fraction of B. trimera shows promising results compared to the positive controls. Our investigations thus contribute to the specialized literature on the use of herbal medicines around nutrition, providing guidance for future studies on these fractions.
... Inflammation is a protective immune response initiated by a host cell against harmful stimuli such as pathogens, the contents of damaged cells, and various chemical and physical irritants [1]. In most tissues, inflammation is initiated by resident macrophages, which recognize various pathogen-and damage-associated molecular patterns, transition to an activated phenotype, and subsequently secrete proinflammatory factors that drive subsequent inflammatory pathways [2]. These responses are mediated by surface receptor activation and downstream activation of the nuclear factor kappa B (NF-κB) and mitogenactivated protein kinase (MAPK) pathways [3]. ...
Resveratrol and its derivative piceid exhibit a wide spectrum of health-promoting bioactivities. A resveratrol-enriched variety of Dongjin rice (DJ526) has been developed by transfection of a resveratrol biosynthesis gene, and increased resveratrol content has been confirmed in seeds following germination. In the current study, these resveratrol-enriched seeds were induced to produce callus, and callus extracts were evaluated for in vitro anti-inflammatory activity. Callus cultures contained greater amounts of resveratrol and piceid than DJ526 seeds, and treatment with DJ526 callus extract significantly reduced the lipopolysaccharide (LPS)-induced production of proinflammatory mediators nitric oxide and prostaglandin E2 by RAW264.7 macrophages. The inflammation-related nuclear factor kappa B and mitogen-activated protein kinase pathways were also inhibited in DJ526 callus extract-treated RAW264.7 cells, resulting in downregulation of proinflammatory factor genes COX-2, iNOS, IL-1β, IL-6, and TNF-α. Expression of the LPS-binding toll-like receptor-4 was also markedly reduced in DJ526 callus extract-treated cells compared to DJ callus extract-treated cells. These findings demonstrate increased resveratrol and piceid content by callus culture of DJ526 rice seeds and the potent anti-inflammatory activity of resveratrol-enriched callus extract.
... Endogenous molecular patterns associated with danger typically represent damaged macromolecules that can accumulate with age as a result of increased production (oxidative stress) and/or insufficient clearance [104,105]. The NLRP3 inflammasome is an important link in the development of the inflammatory response to tissue damage, and during aging, it is an important factor in the development of so-called "inflammaging", when the immune reactions necessary for tissue repair, as damage accumulates, turn into a chronic non-adaptive form [106]. ...
The retinal pigment epithelium (RPE), which ensures the normal functioning of the neural retina, is a pigmented single-cell layer that separates the retina from the Bruch's membrane and the choroid. There are three main types of pigment granules in the RPE cells of the human eye: lipofuscin granules (LG) containing the fluorescent “age pigment” lipofuscin, melanoprotein granules (melanosomes, melanolysosomes) containing the screening pigment melanin and complex melanolipofuscin granules (MLG) containing simultaneously both types of pigments - melanin and lipofuscin. This review examines the functional role of pigment granules in the aging process and in the development of oxidative stress and associated pathologies in RPE cells. The focus is on the process of light-induced oxidative degradation of pigment granules caused by reactive oxygen species. The reasons leading to increased oxidative stress in RPE cells as a result of oxidative degradation of pigment granules are considered. A mechanism has been proposed to explain the phenomenon of age-related decline in melanin content in RPE cells. The essence of the mechanism is that when the lipofuscin part of the melanolipofuscin granule is exposed to light, reactive oxygen species are formed, which destroy its melanin part. As more melanolipofuscin granules are formed with age and the development of degenerative diseases, the melanin in pigmented epithelial cells ultimately disappears.
... Chronic inflammatory diseases can emerge from unchecked acute inflammation [7]. An inflammatory reaction has several components that might result in symptoms and tissue damage [8,9]. Inflammation includes edema, leukocyte infiltration, and granuloma development [10]. ...
The aim of this study is to assess the anti-inflammatory effects of volatile compounds derived from clove bud in vivo and in silico. Clove bud essential oil was obtained through hydrodistillation and subsequently analyzed using GC-MS. The analysis identified ten compounds, which were then subjected to molecular docking with Cyclooxygenase II (PDB ID: 3LN1). From these docking studies, two active compounds were selected for further investigation using a mouse ear edema model induced by DNFB. The results revealed that eugenol was the predominant compound in the essential oil constituting 68.51%. The docking simulations demonstrated effective binding affinities for eugenol and acetyleugenol, with energies of-7.3 and-8.1 Kcal/mol, respectively, which were comparable to aspirin (-7.5 Kcal/mol). Additionally, both selected ligands exhibited non-toxic and non-carcinogenic properties based on ADMET predictions. In the in vivo experiments, significant anti-inflammatory activity was observed for both tested compounds. Notably, 48 hours after the challenge, the presence of acetyleugenol resulted in a more pronounced reduction in ear swelling compared to eugenol. These findings hold promise for potential applications in future clinical studies aimed at harnessing the therapeutic benefits of clove bud derived compounds for anti-inflammatory purposes.
... Different types of stimuli induce different macrophage phenotypes and metabolic profiles, and immune activation can be divided into four main components: inducers (signals that trigger an inflammatory response), sensors (proteins that detect the inducers), mediators (molecules that transmit signals to activate an effector response), and effectors (downstream metabolic programmes that facilitate the maturation of the desired effector phenotype) (7,8). Based on this general classification, the macrophage response to stimulation can be described more clearly. ...
Spinal cord injury (SCI) results in a large amount of tissue cell debris in the lesion site, which interacts with various cytokines, including inflammatory factors, and the intrinsic glial environment of the central nervous system (CNS) to form an inhibitory microenvironment that impedes nerve regeneration. The efficient clearance of tissue debris is crucial for the resolution of the inhibitory microenvironment after SCI. Macrophages are the main cells responsible for tissue debris removal after SCI. However, the high lipid content in tissue debris and the dysregulation of lipid metabolism within macrophages lead to their transformation into foamy macrophages during the phagocytic process. This phenotypic shift is associated with a further pro-inflammatory polarization that may aggravate neurological deterioration and hamper nerve repair. In this review, we summarize the phenotype and metabolism of macrophages under inflammatory conditions, as well as the mechanisms and consequences of foam cell formation after SCI. Moreover, we discuss two strategies for foam cell modulation and several potential therapeutic targets that may enhance the treatment of SCI.
Our laboratory previously extracted bound polyphenols (BPP) in insoluble dietary fiber from navel orange peel (NOP-IDF), and the aim of this study was to investigate the anti-inflammatory activity and potential...
Activation of the NF-κB pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, IκBα-dependent NF-κB termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-κB remain unclear. Here, we showed IκBα-independent rapid termination of nuclear NF-κB mediated by CLK2, which negatively regulated active NF-κB by phosphorylating the RelA/p65 subunit of NF-κB at Ser180 in the nucleus to limit its transcriptional activation through degradation and nuclear export. Depletion of CLK2 increased the production of inflammatory cytokines, reduced viral replication and increased the survival of the mice. Mechanistically, CLK2 phosphorylated RelA/p65 at Ser180 in the nucleus, leading to ubiquitin‒proteasome-mediated degradation and cytoplasmic redistribution. Importantly, a CLK2 inhibitor promoted cytokine production, reduced viral replication, and accelerated murine psoriasis. This study revealed an IκBα-independent mechanism of early-stage termination of NF-κB in which phosphorylated Ser180 RelA/p65 turned off posttranslational modifications associated with transcriptional activation, ultimately resulting in the degradation and nuclear export of RelA/p65 to inhibit excessive inflammatory activation. Our findings showed that the phosphorylation of RelA/p65 at Ser180 in the nucleus inhibits early-stage NF-κB activation, thereby mediating the negative regulation of NF-κB.
Background
Neuroinflammation occurs and develops in neurodegenerative diseases, and the severity of neuroinflammation is closely linked to microglial polarization. Different phenotypes release inflammatory cytokines and perform distinct functions. Modulating microglial polarization to alter neuroinflammation is a potential therapeutic strategy. Currently, human umbilical cord mesenchymal stem cells (hUCMSCs) possess multiple properties of stem cells and can be used in inflammation modulation therapy. Various methods of pre-treatment stem cells have been shown enhance efficacy in disease treatment. Photobiomodulation (PBM), as a non-invasive intervention, has the ability to reduce inflammation.
Methods
Firstly, we constructed a cellular inflammation model to investigate the effect of PBM pre-treatment of hUCMSCs on inflammation and polarization of BV2 cells. We also investigated the effect of the Notch signaling pathway on cells. Secondly, an animal inflammation model was constructed to verify that PBM pre-treatment of hUCMSCs modulated microglia polarization and neuroinflammation.
Results
In our in vitro experiments, PBM pre-treatment of hUCMSCs reduced the release of pro-inflammatory cytokines while promoting the expression of anti-inflammatory cytokine in microglia. The treatment significantly reduced the expression of Notch pathway-related genes in an inflammatory model, facilitated the reduction of M1 phenotype polarization and increased M2 phenotype polarization in microglia. In vivo studies demonstrated that 808 nm light combined with hUCMSCs improved memory behavior in male C57BL/6J mice and significantly reduced the release of pro-inflammatory cytokines in serum and brain tissue while promoting the expression of anti-inflammatory cytokine and the M2 phenotype polarization of microglia.
Conclusions
Overall, our results reveal that photobiomodulation with 808 nm light plays a crucial role in modulating microglial function through its interaction with hUCMSCs, providing novel insights into the molecular mechanism underlying microglial polarization.
Toll-like receptors (TLRs) are crucial components of the innate immune system. Endosomal TLR7 recognizes single-stranded RNAs, yet its endogenous ssRNA ligands are not fully understood. We previously showed that extracellular (ex-) 5′-half molecules of tRNA HisGUG (the 5′-tRNA HisGUG half) in extracellular vesicles (EVs) of human macrophages activate TLR7 when delivered into endosomes of recipient macrophages. Here, we fully explored immunostimulatory ex-5′-tRNA half molecules and identified the 5′-tRNA ValCAC/AAC half, the most abundant tRNA-derived RNA in macrophage EVs, as another 5′-tRNA half molecule with strong TLR7 activation capacity. Levels of the ex-5′-tRNA ValCAC/AAC half were highly up-regulated in macrophage EVs upon exposure to lipopolysaccharide and in the plasma of patients infected with Mycobacterium tuberculosis . The 5′-tRNA ValCAC/AAC half-mediated activation of TLR7 effectively eradicated bacteria infected in macrophages. Mutation analyses of the 5′-tRNA ValCAC/AAC half identified the terminal GUUU sequence as a determinant for TLR7 activation. We confirmed that GUUU is the optimal ratio of guanosine and uridine for TLR7 activation; microRNAs or other RNAs with the terminal GUUU motif can indeed stimulate TLR7, establishing the motif as a universal signature for TLR7 activation. These results advance our understanding of endogenous ssRNA ligands of TLR7 and offer insights into diverse TLR7-involved pathologies and their therapeutic strategies.
Ultrasound has expanded into the therapeutic field as a medical imaging and diagnostic technique. Low-intensity pulsed ultrasound (LIPUS) is a kind of therapeutic ultrasound that plays a vital role in promoting fracture healing, wound repair, immunomodulation, and reducing inflammation. Its anti-inflammatory effects are manifested by decreased pro-inflammatory cytokines and chemokines, accelerated regression of immune cell invasion, and accelerated damage repair. Although the anti-inflammatory mechanism of LIPUS is not very clear, many in vitro and in vivo studies have shown that LIPUS may play its anti-inflammatory role by activating signaling pathways such as integrin/Focal adhesion kinase (FAK)/Phosphatidylinositol 3-kinase (PI3K)/Serine threonine kinase (Akt), Vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS), or inhibiting signaling pathways such as Toll-like receptors (TLRs)/Nuclear factor kappa-B (NF-κB) and p38-Mitogen-activated protein kinase (MAPK). As a non-invasive physical therapy, the anti-inflammatory and immunomodulatory effects of LIPUS deserve further exploration.
The immune system is a complex and fundamental network for organism protection. A minimal unbalance in the host defense system homeostasis can originate severe repercussions in human health. Fundamentally, immune-related diseases can arise from its compromise (immunodeficiency diseases), overactivation against itself (autoimmune diseases) or harmless substances (allergies), and failure of eliminating the harmful agent (chronic inflammation). The notable advances and achievements in the immune system diseases pathophysiology have been allowing for a dramatic improvement of the available treatments. Nevertheless, they present some drawbacks, including the inappropriate benefit/risk ratio. Therefore, there is a strong and urgent need to develop effective therapeutic strategies. Nature is a valuable source of bioactive compounds that can be explored for the development of new drugs. Particularly, plants produce a broad spectrum of secondary metabolites that can be potential prototypes for innovative therapeutic agents. This review describes the immune system and the inflammatory response and examines the current knowledge of eight plants traditionally used as immunomodulatory medicines (Boswellia serrata, Echinacea purpurea, Laurus nobilis, Lavandula angustifolia, Olea europaea, Salvia officinalis, Salvia rosmarinus, and Taraxacum officinale). Moreover, the issues responsible for possible biologic readout inconsistencies (plant species, age, selected organ, developmental stage, growth conditions, geographical location, drying methods, storage conditions, solvent of extraction, and extraction method) will also be discussed. Furthermore, a detailed list of the chemical composition and the immunomodulatory mechanism of action of the bioactive compounds of the selected plant extracts are presented. This review also includes future perspectives and proposes potential new avenues for further investigation.
Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolves the infection and restores mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlates with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, restores mammary tissue normal homeostasis, thus providing evidence for a link between the systemic host response during UTI and mammary gland alterations.
All living organisms must maintain homeostasis to survive, reproduce, and pass their traits on to the next generation. If homeostasis is not maintained, it can result in various diseases and ultimately lead to death. Physiologists have coined the term “homeostasis” to describe this process. With the emergence of immunology as a separate branch of medicine, the concept of immune homeostasis has been introduced. Maintaining immune homeostasis is crucial to support overall homeostasis through different immunological and non-immunological routes. Any changes in the immune system can lead to chronic inflammatory or autoimmune diseases, immunodeficiency diseases, frequent infections, and cancers. Ongoing scientific advances are exploring new avenues in immunology and immune homeostasis maintenance. This chapter introduces the concept of immune homeostasis and its maintenance through different mechanisms.
Our previous study found that glycation with uronic acid‐type reducing sugar enhanced the anti‐inflammatory effect of fish myofibrillar protein (Mf) via the Maillard reaction, and the molecular mechanism of enhanced anti‐inflammatory effect was investigated in this study. Mf was glycated with various reducing sugars at 60 °C and 35% relative humidity. After pepsin‐trypsin digestion, the anti‐inflammatory effects were evaluated by assessing secretions of pro‐inflammatory cytokines and expressions of LPS‐stimulated signalling pathway‐related genes in RAW 264.7 macrophages. Mf glycated with uronic acid‐type reducing sugars: glucuronic acid, galacturonic acid and alginate oligosaccharide, suppressed expression of cd14 and further suppressed expressions of tlr4 and myd88 comparing with intact and glycated Mf with glucose and galactose. Furthermore, uronic acid‐glycated Mf significantly suppressed expressions and secretions of pro‐inflammatory cytokines. The results indicate that uronic acid‐type glycation enhances anti‐inflammatory effect of Mf by attenuating expression of cd14 and enhancing the Mf‐induced suppression in TLR4‐MyD88‐dependent inflammatory signalling pathway.
Macrophages play a critical role in the body’s inflammatory response, and their functions are tightly regulated to ensure optimal immune system function. Here we show that RAS-p110α signalling, a pathway crucially involved in several biological processes and key for tumorigenesis, also exerts regulatory control over two critical aspects of the inflammatory response: monocyte extravasation during the initial stages of the inflammatory response and lysosomal function during the later stages. Disruption of this pathway in a genetically engineered mouse model, or through pharmacological intervention, leads to impaired inflammatory responses and delays resolution, consequently fostering the emergence of more severe and deleterious acute inflammatory reactions in vivo . Our findings shed light on a previously unknown role of the p110α isoform in the regulation of immune inflammatory responses in macrophages, providing a better understanding of the molecular mechanisms underlying the complex regulation of macrophage function in this process. Importantly, given recent evidence of the feasibility of activating p110α with small molecules, our results propose that the RAS-p110α pathway could serve as a promising pharmacological target for the treatment of chronic inflammation. This potential therapeutic avenue holds great promise for alleviating inflammatory disorders and fostering a better quality of life for patients suffering from such conditions.
Oxylipins are signal lipids derived from polyunsaturated fatty acids (PUFAs), which are formed by polyenzymatic multi-acid pathways of danger (cyclooxygenase, lipoxygenase, epoxygenase, anandamide), as well as non-enzymatically. These PUFA transformation pathways are activated in parallel, forming a mixture of active inclusions. Although the combination of oxylipins with tumor secretions was performed a long time ago, the methods of instrumental analysis have only recently been improved, measurements of oxylipins of different classes (profiles) have been compared. The review considers approaches to obtaining the profile of oxylipins by HPLC-MS/MS. The profiles of oxylipins in samples of patients with oncological diseases (breast cancer, colorectal cancer, ovarian cancer, lung cancer, prostate cancer, liver cancer) were compared. The conclusion is made about the possible possibilities of using the profile of blood oxylipins as markers of oncological diseases. Understanding the high level of exceeding the level of PUFAs and the physiological activity of oxylipin mixtures will be accompanied by the perfection of early diagnosis and prediction of the course of tumor diseases.
Previous studies have suggested that exposure to air pollutants may be associated with specific blood indicators or anemia in certain populations. However, there is insufficient epidemiological data and prospective evidence to evaluate the relationship between environmental air pollution and specific types of anemia. We conducted a large-scale prospective cohort study based on the UK Biobank. Annual average concentrations of NO2, PM2.5, PM2.5-10, and PM10 were obtained from the ESCAPE study using the Land Use Regression (LUR) model. The association between atmospheric pollutants and different types of anemia was investigated using the Cox proportional hazards model. Furthermore, restricted cubic splines were used to explore exposure-response relationships for positive associations, followed by stratification and effect modification analyses by gender and age. After adjusting for demographic characteristics, 3-4 of the four types of air pollution were significantly associated with an increased risk of iron deficiency, vitamin B12 deficiency and folate deficiency anemia, while there was no significant association with other defined types of anemia. After full adjustment, we estimated that the hazard ratios (HRs) of iron deficiency anemia associated with each 10 μg/m3 increase in NO2, PM2.5, and PM10 were 1.04 (95%CI: 1.02, 1.07), 2.00 (95%CI: 1.71, 2.33), and 1.10 (95%CI: 1.02, 1.20) respectively. The HRs of folate deficiency anemia with each 10 μg/m3 increase in NO2, PM2.5, PM2.5-10, and PM10 were 1.25 (95%CI: 1.12, 1.40), 4.61 (95%CI: 2.03, 10.47), 2.81 (95%CI: 1.11, 7.08), and 1.99 (95%CI: 1.25, 3.15) respectively. For vitamin B12 deficiency anemia, no significant association with atmospheric pollution was found. Additionally, we estimated almost linear exposure-response curves between air pollution and anemia, and interaction analyses suggested that gender and age did not modify the association between air pollution and anemia. Our research provided reliable evidence for the association between long-term exposure to PM10, PM2.5, PM2.5-10, NO2, and several types of anemia. NO2, PM2.5, and PM10 significantly increased the risk of iron deficiency anemia and folate deficiency anemia. Additionally, we found that the smaller the PM diameter, the higher the risk, and folate deficiency anemia was more susceptible to air pollution than iron deficiency anemia. No association was observed between the four types of air pollution and hemolytic anemia, aplastic anemia, and other types of anemia. Although the mechanisms are not well understood, we emphasize the need to limit the levels of PM and NO2 in the environment to reduce the potential impact of air pollution on folate and iron deficiency anemia.
Reactive oxygen species (ROS) constitute a spectrum of oxygenic metabolites crucial in modulating pathological organism functions. Disruptions in ROS equilibrium span various diseases, and current insights suggest a dual role for ROS in tumorigenesis and the immune response within cancer. This review rigorously examines ROS production and its role in normal cells, elucidating the subsequent regulatory network in inflammation and cancer. Comprehensive synthesis details the documented impacts of ROS on diverse immune cells. Exploring the intricate relationship between ROS and cancer immunity, we highlight its influence on existing immunotherapies, including immune checkpoint blockade, chimeric antigen receptors, and cancer vaccines. Additionally, we underscore the promising prospects of utilizing ROS and targeting ROS modulators as novel immunotherapeutic interventions for cancer. This review discusses the complex interplay between ROS, inflammation, and tumorigenesis, emphasizing the multifaceted functions of ROS in both physiological and pathological conditions. It also underscores the potential implications of ROS in cancer immunotherapy and suggests future research directions, including the development of targeted therapies and precision oncology approaches. In summary, this review emphasizes the significance of understanding ROS‐mediated mechanisms for advancing cancer therapy and developing personalized treatments.
To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of novel chalcone analogues were designed and synthesized. In vitro anti-inflammatory activity of these compounds has been evaluated by...
One of the predictions of the clonal selection theory was the ability of mature peripheral lymphocytes to discriminate between self and nonself. All self-reactive lymphocytes were thought to be deleted during maturation, and any molecule presented to the mature lymphocytes would be regarded as nonself and should therefore induce an adaptive immune response. Indeed, early experiments with model antigens, such as simple chemicals conjugated to self serum proteins and injected with adjuvants showed that responses to such antigens were the norm rather than the exception. However, if unmodified self antigens, and even nonself proteins, were administered alone in the absence of adjuvant, they gave rise to tolerance rather than an immune response. Immune responses specific even for self antigens could be induced, however, if the self antigen was mixed with adjuvants.Although adjuvants have a long history, so far they have only been defined operationally as any substance that increases the immunogenicity of admixed antigens. The reason for the failure of pure antigens to induce immune response is now known—the antigens used in these studies failed to induce the costimulatory signal necessary for the activation of lymphocytes. Accordingly, the mechanism of adjuvant activity has been proposed to be due to the induction of costimulatory signals by microbial constituents carrying PAMPs that are routinely mixed in adjuvants (Janeway 1989xCold Spring Harbor Symp. Janeway, C.A. Jr. Quant. Biol. 1989; 54: 1–13Crossref | PubMedSee all ReferencesJaneway 1989). Recognition of these PAMPs by PRRs is suggested to induce the signals necessary for lymphocyte activation (such as B7) and differentiation (effector cytokines; see above). In other words, adjuvants induce the innate immune system to produce the signals that are required for activation of an adaptive immune response. While adjuvants are potent immunostimulators, most of them cannot be used in the clinic because of unwanted side effects, and much adjuvant research has been directed toward identification of the active components of the adjuvants and their subsequent modification to minimize side effects (for review, seeAudibert and Lise 1993xAudibert, F.M. and Lise, L.D. Immunol. Today. 1993; 14: 281–284Abstract | Full Text PDF | PubMedSee all ReferencesAudibert and Lise 1993). Characterization of the nonclonal receptors of the innate immune system responsible for the adjuvant activity, and, evidently, for the associated side effects, would provide a powerful alternative approach, which would ultimately allow one to target these receptors directly. In one example of such a rational approach, fusion of an antigen with C3dg, a product of complement activation, resulted in dramatic potentiation of a specific immune response to the fused antigen (Dempsey et al 1996xDempsey, P.W., Allison, M.E., Akkaraju, S., Goodnow, C.C., and Fearon, D.T. Science. 1996; 271: 348–350Crossref | PubMedSee all ReferencesDempsey et al 1996).Rational approaches to vaccine design based on the detailed understanding of the molecular mechanisms of innate immunity should ultimately allow one not only to induce a specific adaptive immune response but also the desired effector mechanism without the accompanying damage to the host tissues.
S100/calgranulin polypeptides are present at sites of inflammation, likely released by inflammatory cells targeted to such loci by a range of environmental cues. We report here that receptor for AGE (RAGE) is a central cell surface receptor for EN-RAGE (extracellular newly identified RAGE-binding protein) and related members of the S100/calgranulin superfamily. Interaction of EN-RAGEs with cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Blockade of EN-RAGE/RAGE quenches delayed-type hypersensitivity and inflammatory colitis in murine models by arresting activation of central signaling pathways and expression of inflammatory gene mediators. These data highlight a novel paradigm in inflammation and identify roles for EN-RAGEs and RAGE in chronic cellular activation and tissue injury.
The sensation of pain alerts us to real or impending injury and triggers appropriate protective responses. Unfortunately, pain often outlives its usefulness as a warning system and instead becomes chronic and debilitating. This transition to a chronic phase involves changes within the spinal cord and brain, but there is also remarkable modulation where pain messages are initiated - at the level of the primary sensory neuron. Efforts to determine how these neurons detect pain-producing stimuli of a thermal, mechanical or chemical nature have revealed new signalling mechanisms and brought us closer to understanding the molecular events that facilitate transitions from acute to persistent pain.
Necrosis has been considered a passive form of cell death in which the cell dies as a result of a bioenergetic catastrophe imposed by external conditions. However, in response to alkylating DNA damage, cells undergo necrosis as a self-determined cell fate. This form of death does not require the central apoptotic mediators p53, Bax/Bak, or caspases and actively induces an inflammatory response. Necrosis in response to DNA damage requires activation of the DNA repair protein poly(ADP-ribose) polymerase (PARP), but PARP activation is not sufficient to determine cell fate. Cell death is determined by the effect of PARP-mediated beta-nicotinamide adenine dinucleotide (NAD) consumption on cellular metabolism. Cells using aerobic glycolysis to support their bioenergetics undergo rapid ATP depletion and death in response to PARP activation. In contrast, cells catabolizing nonglucose substrates to maintain oxidative phosphorylation are resistant to ATP depletion and death in response to PARP activation. Because most cancer cells maintain their ATP production through aerobic glycolysis, these data may explain the molecular basis by which DNA-damaging agents can selectively induce tumor cell death independent of p53 or Bcl-2 family proteins.
Bacterial endotoxin [lipopolysaccharide (LPS)] stimulates macrophages to sequentially release early [tumor necrosis factor (TNF)] and late [high mobility group box 1 (HMGB1)] proinflammatory cytokines. The requirement of CD14 and mitogen-activated protein kinases [MAPK; e.g., p38 and extracellular signal-regulated kinase (ERK)1/2] for endotoxin-induced TNF production has been demonstrated previously, but little is known about their involvement in endotoxin-mediated HMGB1 release. Here, we demonstrated that genetic disruption of CD14 expression abrogated LPS-induced TNF production but only partially attenuated LPS-induced HMGB1 release in cultures of primary murine peritoneal macrophages. Pharmacological suppression of p38 or ERK1/2 MAPK with specific inhibitors (SB203580, SB202190, U0126, or PD98059) significantly attenuated LPS-induced TNF production but failed to inhibit LPS-induced HMGB1 release. Consistently, an endogenous, immunosuppressive molecule, spermine, failed to inhibit LPS-induced activation of p38 MAPK and yet, still significantly attenuated LPS-mediated HMGB1 release. Direct suppression of TNF activity with neutralizing antibodies or genetic disruption of TNF expression partially attenuated HMGB1 release from macrophages induced by LPS at lower concentrations (e.g., 10 ng/ml). Taken together, these data suggest that LPS stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms.
A wide variety of pathogenic microorganisms have been demonstrated to cause eukaryotic cell death, either as a consequence of infecting host cells or by producing toxic products. Pathogen-induced host cell death has been characterized as apoptosis in many of these systems. It is increasingly being recognized that cell death with some of the features of apoptosis may result from a variety of molecular pathways and that experimental techniques used to identify cell death often do not distinguish among these mechanisms. We propose that a clear understanding of the diversity of processes mediating cell death has been obscured by the simplicity of the nomenclature system commonly employed to describe eukaryotic cell death. This review presents a perspective on eukaryotic cell death and discusses experimental techniques used to study these processes.
Interactions between ligands and receptors are central to communication between cells and tissues. Human airway epithelia constitutively produce both a ligand, the growth factor heregulin, and its receptors--erbB2, erbB3 and erbB4 (refs 1-3). Although heregulin binding initiates cellular proliferation and differentiation, airway epithelia have a low rate of cell division. This raises the question of how ligand-receptor interactions are controlled in epithelia. Here we show that in differentiated human airway epithelia, heregulin-alpha is present exclusively in the apical membrane and the overlying airway surface liquid, physically separated from erbB2-4, which segregate to the basolateral membrane. This physical arrangement creates a ligand-receptor pair poised for activation whenever epithelial integrity is disrupted. Indeed, immediately following a mechanical injury, heregulin-alpha activates erbB2 in cells at the edge of the wound, and this process hastens restoration of epithelial integrity. Likewise, when epithelial cells are not separated into apical and basolateral membranes ('polarized'), or when tight junctions between adjacent cells are opened, heregulin-alpha activates its receptor. This mechanism of ligand-receptor segregation on either side of epithelial tight junctions may be vital for rapid restoration of integrity following injury, and hence critical for survival. This model also suggests a mechanism for abnormal receptor activation in diseases with increased epithelial permeability.
Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.
Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.
Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes promote the switch of arachidonic acid-derived prostaglandins and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3 polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. Consequently, apoptotic neutrophils undergo phagocytosis by macrophages, leading to neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor-beta1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics. Understanding these and further details of the mechanism required for inflammation resolution may underpin the development of drugs that can resolve inflammatory processes in directed and controlled ways.
A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.
Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.
Scientists who study neutrophils often have backgrounds in cell biology, biochemistry, haematology, rheumatology or infectious disease. Paradoxically, immunologists seem to have a harder time incorporating these host-defence cells into the framework of their discipline. The recent literature discussed here indicates that it is appropriate for immunologists to take as much interest in neutrophils as in their lymphohaematopoietic cousins with smooth nuclei. Neutrophils inform and shape immune responses, contribute to the repair of tissue as well as its breakdown, use killing mechanisms that enrich our concepts of specificity, and offer exciting opportunities for the treatment of neoplastic, autoinflammatory and autoimmune disorders.
The development of lymphoid organs can be viewed as a continuum. At one end are the 'canonical' secondary lymphoid organs, including lymph nodes and spleen; at the other end are 'ectopic' or tertiary lymphoid organs, which are cellular accumulations arising during chronic inflammation by the process of lymphoid neogenesis. Secondary lymphoid organs are genetically 'preprogrammed' and 'prepatterned' during ontogeny, whereas tertiary lymphoid organs arise under environmental influences and are not restricted to specific developmental 'windows' or anatomic locations. Between these two boundaries are other types of lymphoid tissues that are less developmentally but more environmentally regulated, such as Peyer's patches, nasal-associated lymphoid tissue, bronchial-associated lymphoid tissue and inducible bronchial-associated lymphoid tissue. Their regulation, functions and potential effects are discussed here.
Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.
It is well known that, in large populations, HDL-cholesterol levels are inversely related to the risk of atherosclerotic clinical events; however, in an individual, the predictive value of an HDL-cholesterol level is far from perfect. As a result, other HDL-associated factors have been investigated, including the quality and function of HDL in contradistinction to the level of HDL-cholesterol. Regarding their quality, HDL particles are highly heterogeneous and contain varying levels of antioxidants or pro-oxidants, which results in variation in HDL function. It has been postulated that HDL functions to promote reverse cholesterol transport. Recent studies support this role for HDL but also indicate that HDL is a modulator of systemic inflammation. In the absence of inflammation, HDL has a complement of antioxidant enzymes that work to maintain an anti-inflammatory state. In the presence of systemic inflammation, these antioxidant enzymes can be inactivated and HDL can accumulate oxidized lipids and proteins that make it proinflammatory. Under these conditions the main protein of HDL, apolipoprotein A-I, can be modified by reactive oxygen species. This modification impairs the ability of HDL to promote cholesterol efflux by the ATP-binding cassette transporter A-1 pathway. Animal studies and small-scale human studies suggest that measures of the quality and novel functions of HDL might provide an improved means of identifying subjects at increased risk for atherosclerotic events, compared with the current practice of only measuring HDL-cholesterol levels. The quality and function of HDL are also attractive targets for emerging therapies.
Multicellular animals detect pathogens via a set of receptors that recognize pathogen-associated molecular patterns (PAMPs). However, pathogens are not the only causative agents of tissue and cell damage: trauma is another one. Evidence is accumulating that trauma and its associated tissue damage are recognized at the cell level via receptor-mediated detection of intracellular proteins released by the dead cells. The term "alarmin" is proposed to categorize such endogenous molecules that signal tissue and cell damage. Intriguingly, effector cells of innate and adaptive immunity can secrete alarmins via nonclassical pathways and often do so when they are activated by PAMPs or other alarmins. Endogenous alarmins and exogenous PAMPs therefore convey a similar message and elicit similar responses; they can be considered subgroups of a larger set, the damage-associated molecular patterns (DAMPs).
A hallmark of tissue injury and repair is the turnover of extracellular matrix components. This review focuses on the role of the glycosaminoglycan hyaluronan in tissue injury and repair. Both the synthesis and degradation of extracellular matrix are critical contributors to tissue repair and remodeling. Fragmented hyaluronan accumulates during tissue injury and functions in ways distinct from the native polymer. There is accumulating evidence that hyaluronan degradation products can stimulate the expression of inflammatory genes by a variety of immune cells at the injury site. CD44 is the major cell-surface hyaluronan receptor and is required to clear hyaluronan degradation products produced during lung injury; impaired clearance of hyaluronan results in persistent inflammation. However, hyaluronan fragment stimulation of inflammatory gene expression is not dependent on CD44 in inflammatory macrophages. Instead, hyaluronan fragments utilize both Toll-like receptor (TLR) 4 and TLR2 to stimulate inflammatory genes in macrophages. Hyaluronan also is present on the cell surface of lung alveolar epithelial cells and provides protection against tissue damage by interacting with TLR2 and TLR4 on these parenchymal cells. The simple repeating structure of hyaluronan appears to be involved in a number of important aspects of noninfectious tissue injury and repair that are dependent on the size and location of the polymer as well as the interacting cells. Thus, the interactions between the endogenous matrix component hyaluronan and its signaling receptors initiate inflammatory responses, maintain structural cell integrity, and promote recovery from tissue injury.
Forkhead box O (FoxO) transcription factors FoxO1, FoxO3a, FoxO4 and FoxO6, the mammalian orthologs of Caenorhabditis elegans DAF-16, are emerging as an important family of proteins that modulate the expression of genes involved in apoptosis, the cell cycle, DNA damage repair, oxidative stress, cell differentiation, glucose metabolism and other cellular functions. FoxO proteins are regulated by multiple mechanisms. They undergo inhibitory phosphorylation by protein kinases such as Akt, SGK, IKK and CDK2 in response to external and internal stimuli. By contrast, they are activated by upstream regulators such as JNK and MST1 under stress conditions. Their activities are counterbalanced by the acetylases CBP and p300 and the deacetylase SIRT1. Also, whereas polyubiquitylation of FoxO1 and FoxO3a leads to their degradation by the proteasome, monoubiquitylation of FoxO4 facilitates its nuclear localization and augments its transcriptional activity. Thus, the potent functions of FoxO proteins are tightly controlled by complex signaling pathways under physiological conditions; dysregulation of these proteins may ultimately lead to disease such as cancer.
Werner, Sabine, and Richard Grose. Regulation of Wound Healing by Growth Factors and Cytokines. Physiol Rev 83: 835–870, 2003; 10.1152/physrev.00032.2002.—Cutaneous wound healing is a complex process involving blood clotting, inflammation, new tissue formation, and finally tissue remodeling. It is well described at the histological level, but the genes that regulate skin repair have only partially been identified. Many experimental and clinical studies have demonstrated varied, but in most cases beneficial, effects of exogenous growth factors on the healing process. However, the roles played by endogenous growth factors have remained largely unclear. Initial approaches at addressing this question focused on the expression analysis of various growth factors, cytokines, and their receptors in different wound models, with first functional data being obtained by applying neutralizing antibodies to wounds. During the past few years, the availability of genetically modified mice has allowed elucidation of the function of various genes in the healing process, and these studies have shed light onto the role of growth factors, cytokines, and their downstream effectors in wound repair. This review summarizes the results of expression studies that have been performed in rodents, pigs, and humans to localize growth factors and their receptors in skin wounds. Most importantly, we also report on genetic studies addressing the functions of endogenous growth factors in the wound repair process.
An adaptationist programme has dominated evolutionary thought in England and the United States during the past 40 years. It is based on faith in the power of natural selection as an optimizing agent. It proceeds by breaking an oragnism into unitary 'traits' and proposing an adaptive story for each considered separately. Trade-offs among competing selective demands exert the only brake upon perfection; non-optimality is thereby rendered as a result of adaptation as well. We criticize this approach and attempt to reassert a competing notion (long popular in continental Europe) that organisms must be analysed as integrated wholes, with Baupläne so constrained by phyletic heritage, pathways of development and general architecture that the constraints themselves become more interesting and more important in delimiting pathways of change than the selective force that may mediate change when it occurs. We fault the adaptationist programme for its failure to distinguish current utility from reasons for origin (male tyrannosaurs may have used their diminutive front legs to titillate female partners, but this will not explain why they got so small); for its unwillingness to consider alternatives to adaptive stories; for its reliance upon plausibility alone as a criterion for accepting speculative tales; and for its failure to consider adequately such competing themes as random fixation of alleles, production of non-adaptive structures by developmental correlation with selected features (allometry, pleiotropy, material compensation, mechanically forced correlation), the separability of adaptation and selection, multiple adaptive peaks, and current utility as an epiphenomenon of non-adaptive structures. We support Darwin's own pluralistic approach to identifying the agents of evolutionary change.
The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis, physiological cell death, programmed cell death, chromatolysis (the first name of apoptosis in 1914), karyorhexis, karyolysis, and cell suicide, of which there are three forms: by lysosomes, by free radicals, and by a genetic mechanism (apoptosis). Some of the typical features of apoptosis are discussed, such as budding (as opposed to blebbing and zeiosis) and the inflammatory response. For cell death not by apoptosis the most satisfactory term is accidental cell death. Necrosis is commonly used but it is not appropriate, because it does not indicate a form of cell death but refers to changes secondary to cell death by any mechanism, including apoptosis. Abundant data are available on one form of accidental cell death, namely ischemic cell death, which can be considered an entity of its own, caused by failure of the ionic pumps of the plasma membrane. Because ischemic cell death (in known models) is accompanied by swelling, the name oncosis is proposed for this condition. The term oncosis (derived from onkos, meaning swelling) was proposed in 1910 by von Reckling-hausen precisely to mean cell death with swelling. Oncosis leads to necrosis with karyolysis and stands in contrast to apoptosis, which leads to necrosis with karyorhexis and cell shrinkage.
The regulation of the transcription factor NF-κB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-κB regulation is the IκB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-κB and IKK.
The interaction of glucose-modified and inflammation-promoting ligands with the receptor for advanced glycation end products (RAGE) is emerging as a central mechanism contributing to the diverse complications of diabetes. These ligands, particularly in oligomeric form, bind to RAGE and transduce intracellular signals. The consequences of this interaction, as elucidated in cultured cells and animal models, include upregulation of inflammatory and tissue-degradative pathways. Pharmacologic antagonism of RAGE may hold promise for the treatment of diabetic complications.
The presence of Leptopilina heterotoma or Leptopilina boulardi eggs in the hemocoel of a Drosophila melanogaster larva induces the differentiation of lamellocytes, the blood cells that encapsulate foreign objects. L. boulardi eggs are encapsulated by the newly differentiated lamellocytes, but L. heterotoma eggs are not. The induced lamellocytes in host larvae with L. heterotoma eggs undergo the same destructive morphological changes as reported previously for lamellocytes present in melanotic tumor mutant larvae at the time of parasitization. Thus, the virus-like particles produced by the L. heterotoma female to protect its eggs from encapsulation do not block the differentiation of lamellocytes, but rather destroy lamellocytes whenever they are present in the hemocoel.
The purpose of this overview is to recount certain new insights as to low inflmmatory reactions develop. In particular, we will highlight several ways in which vascular endothelial cells may actively participate in these processes
IN this seminar we review recent studies suggesting that the central pathologic features of diabetic complications are caused by the hyperglycemia-accelerated formation of nonenzymatic advanced glycosylation end products in tissue. We will emphasize new research findings with important clinical implications, since older information is available in previously published reviews.1 , 2 Other biochemical mechanisms by which hyperglycemia may contribute to the development of diabetic complications are not discussed here, since they are comprehensively reviewed elsewhere.3 4 5 6 7 8 Differences between Early and Advanced Glycosylation Products The central pathophysiologic features of diabetic vascular complications are an abnormal leakage of proteins from the circulation and a progressive . . .
The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis, physiological cell death, programmed cell death, chromatolysis (the first name of apoptosis in 1914), karyorhexis, karyolysis, and cell suicide, of which there are three forms: by lysosomes, by free radicals, and by a genetic mechanism (apoptosis). Some of the typical features of apoptosis are discussed, such as budding (as opposed to blebbing and zeiosis) and the inflammatory response. For cell death not by apoptosis the most satisfactory term is accidental cell death. Necrosis is commonly used but it is not appropriate, because it does not indicate a form of cell death but refers to changes secondary to cell death by any mechanism, including apoptosis. Abundant data are available on one form of accidental cell death, namely ischemic cell death, which can be considered an entity of its own, caused by failure of the ionic pumps of the plasma membrane. Because ischemic cell death (in known models) is accompanied by swelling, the name oncosis is proposed for this condition. The term oncosis (derived from ónkos, meaning swelling) was proposed in 1910 by von Reckling-hausen precisely to mean cell death with swelling. Oncosis leads to necrosis with karyolysis and stands in contrast to apoptosis, which leads to necrosis with karyorhexis and cell shrinkage.
Glucocorticoids are hormone products of the adrenal gland, which have long been recognized to have a profound impact on immunologic processes. The communication between immune and neuroendocrine systems is, however, bidirectional. The endocrine and immune systems share a common "chemical language," with both systems possessing ligands and receptors of "classical" hormones and immunoregulatory mediators. Studies in the early to mid 1980s demonstrated that monocyte-derived or recombinant interleukin-1 (IL-1) causes secretion of hormones of the hypothalamic-pituitary-adrenal (HPA) axis, establishing that immunoregulators, known as cytokines, play a pivotal role in this bidirectional communication between the immune and neuroendocrine systems. The subsequent 10-15 years have witnessed demonstrations that numerous members of several cytokine families increase the secretory activity of the HPA axis. Because this neuroendocrine action of cytokines is mediated primarily at the level of the central nervous system, studies investigating the mechanisms of HPA activation produced by cytokines take on a more broad significance, with findings relevant to the more fundamental question of how cytokines signal the brain. This article reviews published findings that have documented which cytokines have been shown to influence hormone secretion from the HPA axis, determined under what physiological/pathophysiological circumstances endogenous cytokines regulate HPA axis activity, established the possible sites of cytokine action on HPA axis hormone secretion, and identified the potential neuroanatomic and pharmacological mechanisms by which cytokines signal the neuroendocrine hypothalamus.
The regulation of the transcription factor NF-kappaB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-kappaB regulation is the IkappaB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK.
Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, if targeted destruction and assisted repair are not properly phased, inflammation can lead to persistent tissue damage by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms of its checkpoints, where binary or higher-order signals drive each commitment to escalate, go signals trigger stop signals, and molecules responsible for mediating the inflammatory response also suppress it, depending on timing and context. The non-inflammatory state does not arise passively from an absence of inflammatory stimuli; rather, maintenance of health requires the positive actions of specific gene products to suppress reactions to potentially inflammatory stimuli that do not warrant a full response.
The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.
Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
Plasticity and functional polarization are hallmarks of the mononuclear phagocyte system. Here we review emerging key properties of different forms of macrophage activation and polarization (M1, M2a, M2b, M2c), which represent extremes of a continuum. In particular, recent evidence suggests that differential modulation of the chemokine system integrates polarized macrophages in pathways of resistance to, or promotion of, microbial pathogens and tumors, or immunoregulation, tissue repair and remodeling.
We have identified cellular and molecular features of the stem cell niche required for marked amplification of mouse colonic epithelial progenitors (ColEPs) that occurs in response to wounding of the epithelium with dextran sodium sulfate. This regenerative response in areas adjacent to breaches in the epithelial barrier depends on the gut microbiota because ColEP proliferation is markedly diminished in germ-free animals. Analysis of conventionally raised C57BL/6 (B6) knockout mice lacking the Toll-like receptor signal transduction pathway component Myd88 and wild-type animals transplanted with Myd88(-/-) bone marrow, revealed that Myd88-mediated signaling through mesenchymal cells is also required for the ColEP response. Studies of B6 Csf1(op/op) (lacking macrophages) mice, Rag1(-/-) mice, and wild-type mice treated with neutrophil-specific Gr1 mAbs, disclosed that macrophages but not lymphocytes or neutrophils are necessary. GeneChip analysis of laser-capture-microdissected mesenchymal cells coupled with immunohistochemical and electron microscopic studies showed that, during the regenerative response, macrophages in the pericryptal stem cell niche express genes associated with their activation and extend processes to directly contact ColEPs near the crypt base. GeneChip analysis also identified a number of potential molecular mediators of regeneration expressed in the pericryptal progenitor niche, including secreted factors that stimulate epithelial proliferation and proteins involved in extracellular matrix and basement membrane function, stability, and growth factor binding. Together, these studies indicate that the colonic epithelial progenitor niche is a dynamic structure in which macrophages function as mobile "cellular transceivers" that coordinate inputs from luminal microbes and injured epithelium and transmit regenerative signals to neighboring ColEPs.
The identification of bone marrow-derived endothelial progenitor cells has altered our understanding of new blood vessel growth and tissue regeneration. Previously, new blood vessel growth in the adult was thought to only occur through angiogenesis, the sprouting of new vessels from existing structures. However, it has become clear that circulating bone marrow-derived cells can form new blood vessels through a process of postnatal vasculogenesis, with endothelial progenitor cells selectively recruited to injured or ischemic tissue. How this process occurs has remained unclear. One common element in the different environments where vasculogenesis is believed to occur is the presence of a hypoxic stimulus. We have identified the chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 as critical mediators for the ischemia-specific recruitment of circulating progenitor cells. We have found that the endothelial expression of SDF-1 acts as a signal indicating the presence of tissue ischemia, and that its expression is directly regulated by hypoxia-inducible factor-1. Stromal cell-derived factor 1 is the only chemokine family member known to be regulated in this manner. Later events, including proliferation, patterning, and assembly of recruited progenitors into functional blood vessels, are also influenced by tissue oxygen tension and hypoxia. Interestingly, both SDF-1 and hypoxia are present in the bone marrow niche, suggesting that hypoxia may be a fundamental requirement for progenitor cell trafficking and function. As such, ischemic tissue may represent a conditional stem cell niche, with recruitment and retention of circulating progenitors regulated by hypoxia through differential expression of SDF-1.
High mobility group box 1 (HMGB1), originally described as a DNA-binding protein, can also be released extracellularly and functions as a late mediator of inflammatory responses. Although recent reports have indicated that the receptor for advanced glycation end products (RAGE) as well as Toll-like receptor (TLR)2 and TLR4 are involved in cellular activation by HMGB1, there has been little evidence of direct association between HMGB1 and these receptors. To examine this issue, we used fluorescence resonance energy transfer (FRET) and immunoprecipitation to directly investigate cell surface interactions of HMGB1 with TLR2, TLR4, and RAGE. FRET images in RAW264.7 macrophages demonstrated association of HMGB1 with TLR2 and TLR4 but not RAGE. Transient transfections into human embryonic kidney-293 cells showed that HMGB1 induced cellular activation and NF-kappaB-dependent transcription through TLR2 or TLR4 but not RAGE. Coimmunoprecipitation also found interaction between HMGB1 and TLR2 as well as TLR4, but not with RAGE. These studies provide the first direct evidence that HMGB1 can interact with both TLR2 and TLR4 and also supply an explanation for the ability of HMGB1 to induce cellular activation and generate inflammatory responses that are similar to those initiated by LPS.
The mononuclear phagocyte system (MPS) has been defined as a family of cells comprising bone marrow progenitors, blood monocytes and tissue macrophages. Macrophages are a major cell population in most of the tissues in the body, and their numbers increase further in inflammation, wounding and malignancy. Their trophic roles for other cell types in development and homeostasis are becoming increasingly evident. The receptor for macrophage colony-stimulating factor (CSF-1R) is expressed in a large proportion of cells considered to be mononuclear phagocytes, including antigen-presenting dendritic cells, which can be considered a specialized adaptive state rather than a separate lineage. The unity of the MPS is challenged by evidence that there is a separate embryonic phagocyte lineage, by the transdifferentiation and fusion of MPS cells with other cell types, and by evidence of local renewal of tissue macrophage populations as opposed to monocyte recruitment. The concept of the MPS may have partly outlived its usefulness.
Organismal homeostasis depends on an intricate balance between cell death and renewal. Early pathologists recognized that this balance could be disrupted by the extensive damage observed in internal organs during the course of certain diseases. This form of tissue damage was termed "necrosis", derived from the Greek "nekros" for corpse. As it became clear that the essential building block of tissue was the cell, necrosis came to be used to describe pathologic cell death. Until recently, necrotic cell death was believed to result from injuries that caused an irreversible bioenergetic compromise. The cell dying by necrosis has been viewed as a victim of extrinsic events beyond its control. However, recent evidence suggests that a cell can initiate its own demise by necrosis in a manner that initiates both inflammatory and/or reparative responses in the host. By initiating these adaptive responses, programmed cell necrosis may serve to maintain tissue and organismal integrity.
Macrophages within the tumor microenvironment facilitate angiogenesis and extracellular-matrix breakdown and remodeling and promote tumor cell motility. Recent studies reveal that direct communication between macrophages and tumor cells leads to invasion and egress of tumor cells into the blood vessels (intravasation). Thus, macrophages are at the center of the invasion microenvironment and are an important drug target for cancer therapy.
Clinical and epidemiologic studies have suggested an association between infectious agents and chronic inflammatory disorders and cancer. Better understanding of microbial pattern-recognition receptors and innate immune signaling pathways of the host is helping to elucidate the connection between microbial infection and chronic disease. We propose that a key aspect of pathogenesis is an aberrant epithelial barrier that can be instigated by microbial toxins, environmental insults, or the genetic predisposition of the host. Loss of epithelial integrity results in activation of resident inflammatory cells by microbial invaders or endogenous ligands. When coupled with a failure of normal control mechanisms that limit leukocyte activation, a cascade is established that induces chronic inflammation and its consequences. Here, we outline this mechanistic framework and briefly review how alteration of innate immune response genes in murine models can provide insights into the potential microbial origins of diverse conditions including Crohn's disease, psoriasis, atherosclerosis, diabetes, and liver cancer.
Cell deletion is a physiological process for the development and maintenance of tissue homeostasis in metazoa. This is mainly achieved by the induction of various forms of programmed cell death followed by the recognition and removal of the targeted cells by phagocytes. In this review, we will discuss cell deletion in relation to the development and function of the innate immune system, particularly of the mononuclear phagocyte system (MPS), its ontogeny and potential role in tissue remodeling in the embryo and adult. Ongoing studies are addressing the roles of professional phagocytes of the MPS and neighboring tissue cells in dying cell removal, and candidate molecules that might attract mononuclear phagocytes to the dying cells. The potential phagocyte must discriminate between living and dying cells; current concepts for this discrimination derive from the observation of newly exposed ligands on the dying cells and new evidence for direct inhibition of uptake by viable cells.
Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease.
Resolution of inflammation and the return of tissues to homeostasis are essential. Efforts to identify molecular events governing termination of self-limited inflammation uncovered pathways in resolving exudates that actively generate, from essential omega fatty acids, new families of local-acting mediators. These chemical mediator families, termed resolvins and protectins, are potent stereoselective agonists that control the duration and magnitude of inflammation, joining the lipoxins as signals in resolution. This review examines the mapping of these circuits and recent advances in our understanding of the biosynthesis and actions of these novel proresolving lipid mediators. Aspirin jump-starts resolution by triggering biosynthesis of specific epimers of these mediators. In addition to their origins in inflammation resolution, these compounds also display potent protective roles in neural systems, liver, lung, and eye. Given the potent actions of lipoxins, resolvins, and protectins in models of human disease, deficiencies in resolution pathways may contribute to many diseases and offer exciting new potential for therapeutic control via resolution.
Cutaneous wound healing is a complex process involving blood clotting, inflammation, new tissue formation, and finally tissue remodeling. It is well described at the histological level, but the genes that regulate skin repair have only partially been identified. Many experimental and clinical studies have demonstrated varied, but in most cases beneficial, effects of exogenous growth factors on the healing process. However, the roles played by endogenous growth factors have remained largely unclear. Initial approaches at addressing this question focused on the expression analysis of various growth factors, cytokines, and their receptors in different wound models, with first functional data being obtained by applying neutralizing antibodies to wounds. During the past few years, the availability of genetically modified mice has allowed elucidation of the function of various genes in the healing process, and these studies have shed light onto the role of growth factors, cytokines, and their downstream effectors in wound repair. This review summarizes the results of expression studies that have been performed in rodents, pigs, and humans to localize growth factors and their receptors in skin wounds. Most importantly, we also report on genetic studies addressing the functions of endogenous growth factors in the wound repair process.
Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.