Schematic of the basic structure of lipopolysaccharide. LPS consists of three regions: from the bottom, lipid A (chair structure indicates di-glucosamine headgroup, red circles indicate phosphate groups, squiggly lines indicate acyl chains), core sugars, and O-antigen, which consists of repeating units (denoted in brackets, with an “n”) of oligosaccharides.

Schematic of the basic structure of lipopolysaccharide. LPS consists of three regions: from the bottom, lipid A (chair structure indicates di-glucosamine headgroup, red circles indicate phosphate groups, squiggly lines indicate acyl chains), core sugars, and O-antigen, which consists of repeating units (denoted in brackets, with an “n”) of oligosaccharides.

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Lipopolysaccharide (LPS) is a component of the outer membrane of almost all Gram-negative bacteria and consists of lipid A, core sugars, and O-antigen. LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokine...

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Lipopolysaccharides (LPS) make up approximately 75% of the Gram-negative bacterial outer membrane (OM) surface, however, due to the complexity of the molecule, there are very few model OMs that include LPS. The LPS molecule consists of lipid A, which anchors the LPS within the OM, a core polysaccharide region and a variable O-antigen polysaccharide...

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... In this context, it has been reported that the LPS contained in the vesicles is important for the induction of a pro-inflammatory immune response by activating immune cells such as monocytes and macrophages, in addition to triggering a humoral response. These properties enable the LPSs to direct an adaptive immune response, which allows for the conceptualization of microvesicles as carriers of epitopes for the development of attenuated or inactivated vaccines toward microorganisms [170]. However, LPSs are also a limiting factor for the use of OMVs in vaccine construction, as their excessive toxicity can lead to septic shock [130]. ...
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Changes in population demographics indicate that the elderly population will reach 2.1 billion worldwide by 2050. In parallel, there will be an increase in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. This review explores dysbiosis occurring in these pathologies and how virulence factors contribute to the worsening or development of clinical conditions, and it summarizes existing and potential ways to combat microorganisms related to these diseases. Microbiota imbalances can contribute to the progression of neurodegenerative diseases by increasing intestinal permeability, exchanging information through innervation, and even acting as a Trojan horse affecting immune cells. The microorganisms of the microbiota produce virulence factors to protect themselves from host defenses, many of which contribute to neurodegenerative diseases. These virulence factors are expressed according to the genetic composition of each microorganism, leading to a wide range of factors to be considered. Among the main virulence factors are LPS, urease, curli proteins, amyloidogenic proteins, VacA, and CagA. These factors can also be packed into bacterial outer membrane vesicles, which transport proteins, RNA, and DNA, enabling distal communication that impacts various diseases, including Alzheimer’s and Parkinson’s.
... LPS is a major component of the outer membrane of Gram-negative bacteria, and lipid A is the center of toxicity of LPS that determines its immune response (Hankins & Trent, 2009). LPS can be recognized by Toll-like receptor 4 (TLR4) on the cell surface in the internal circulatory system, and TLR4 interacts with the junction protein MyD88, causing the activation of signaling pathways, which ultimately leads to the activation of NF-κB, and consequently induces an inflammatory immune response in hepatocytes (Maeshima & Fernandez, 2013;Tang et al., 2018Tang et al., , 2023. ...
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Gut bacterial lipopolysaccharide (LPS) could be released into the circulatory system via the gut–liver axis and cause inflammatory immune response, while Cordyceps militaris polysaccharide (CMP40) has been reported to be effective in alleviating this inflammatory response. In this study, the effects of CMP40 gut fermentation on internal LPS structure formation and the subsequent immune response were explored. Results showed that CMP40 could change antigenicity of LPS of Vibrio parahaemolyticus, Salmonella enterica, and enterotoxigenic Escherichia coli, indicated by a reduced level of NO, IL‐1β, IL‐6, and TNF‐α. The LPS structure of these three strains were further elucidated. ESI/MS results revealed that CMP40 fermentation could alter the LPS structure by removing phosphate group from a single Kdo sugar or removing additional sided fatty acid chain. The gene expressions of enzymes that are responsible for group transfer further confirmed this structure modification process. This study focused on the regulation of polysaccharide on gut bacteria LPS and provided a new insight into health effect of CMP40.
... TLR4 (toll-like receptor 4) is a receptor that recognizes LPS (lipopolysaccharide), a type of glycolipid present in the cell walls of gramnegative bacteria such as Escherichia coli [213][214][215][216]. LPS, also known as endotoxin, is a potent mediator of inflammation, and TLR4 is widely recognized as a receptor that plays a pivotal role in the inflammatory response induced by LPS. ...
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β-glucans consisting of β-(1,3)-linked glucose as the main chain (hereafter simply called “β-glucan”) are suggested to have the potential for many beneficial effects on health. Among known beneficial effects, the most notable effect of β-glucan would be the antitumor effect. The antitumor effect of β-glucan has been known since the mid-twentieth century. In current cancer treatments where immune checkpoint inhibitors are attracting attention, it is expected that the combined administration of β-glucan will exhibit a greater therapeutic effect. The antitumor effect of β-glucan is believed to be closely linked to the receptors that recognize β-glucan. On the other hand, it has been clarified that there are many receptors for the recognition of β-glucan, in addition to CR3 (complement receptor 3) and dectin-1 (dendritic cell-associated C-type lectin-1), the well-known β-glucan receptors. This review focused on various β-glucan receptors reported previously and discusses the molecular mechanisms through which β-glucans exhibit antitumor effects.
... The lipid A moiety of monomeric LPS is the inflammatory component. 52 Recognition of LPS by the immune system and initiation of an inflammatory response relies on the stepwise binding of LPS to LPS binding protein (LBP) resulting in its conversion to the monomeric active form, followed by binding to cell a surface receptor complex of TLR4/MD2 and CD14 on myeloid cells. 53 Assembly of a bipartite signalling complex composed of MyD88/TIRAP and TRAM/ TRIF can activate cytokines (IL-1β, IL-6 and TNFα) and IFNβ production, respectively. ...
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This review focuses on a special aspect of hepatic lipid storage and inflammation that occurs during nutritional excess in obesity. Mounting evidence supports that prolonged excess fatty acid (FA) uptake in the liver is strongly associated with hepatic lipid storage and inflammation and that the two processes are closely linked by a homeostatic mechanism. There is also strong evidence that bacterial lipids may enter the gut by a common mechanism with lipid absorption and that there is a set point to determine when their uptake triggers an inflammatory response in the liver. In fact, the progression from high uptake of FAs in the liver resulting in Metabolic dysfunction‐associated steatotic liver disease (MASLD) to the development of the more serious Metabolic dysfunction‐associated steatohepatitis (MASH) depends on the degree of inflammation and its progression from an acute to a chronic state. Thus, MASLD/MASH implicates both excess fatty acids and progressive inflammation in the aetiology of liver disease. We start the discussion by introduction of CD36, a major player in FA and lipopolysaccharide (LPS) uptake in the duodenum, liver and adipose tissue. We will then introduce CEACAM1, a major player in the regulation of hepatic de novo lipogenesis and the inflammatory response in the liver, and its dual association with CD36 in enterocytes and hepatocytes. We conclude that CEACAM1 and CD36 together regulate lipid droplet formation and inflammation in the liver.
... As OMVs represent with minor modifications the bacterial outer membrane, they are composed of a large array of bacterial antigens, including the molecules encapsulated in their lumen; these are mostly periplasmic proteins, occasionally flagellin [87][88][89] as well as ribosomal RNA and ss or dsDNA fractions [10,11,13,14]. The PAMPs of the majority of these antigens bind on seven receptors, of which two are endocytic [ [63,93]. TLR 5 reacts with flagellin, and TLR 9 and TLR 13 recognize unmethylated CpG and ribosomal RNA, respectively [94,95]. ...
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The attractiveness of OMVs derived from Gram-negative bacteria lies in the fact that they have two biomembranes sandwiching a peptidoglycan layer. It is well known that the envelope of OMVs consists of the outer bacterial membrane [OM] and not of the inner one [IM] of the source bacterium. This implies that all outer membranous molecules found in the OM act as antigens. However, under specific conditions, some of the inner membrane proteins can be exported into the outer membrane layer and perform as antigens. A key information was that the used purification procedures for OMVs, the induction methods to increase the production of OMVs as well as the specific mutant strains obtained via genetic engineering affect the composition of potential antigens on the surface and in the lumen of the OMVs. The available literature allowed us to list the major antigens that could be defined on OMVs. The functions of the antigens within the source bacterium are discussed for a better understanding of the various available hypotheses on the biogenesis of vesicle formation. Also, the impacts of OMV antigens on the immune system using animal models are assessed. Furthermore, information on the pathways of OMVs entering the host cell is presented. An example of a bacterial infection that causes epidemic diseases, namely via Neisseria meningitidis, is used to demonstrate that OMVs derived from this pathogen elicit protective immune responses when administered as a vaccine. Furthermore, information on OMV vaccines under development is presented. The assembled knowledge allowed us to formulate a number of reasons why OMVs are attractive as vaccine platforms, as their undesirable side effects remain small, and to provide an outlook on the potential use of OMVs as a vaccine platform.
... Several structural elements of lipid A are known to critically influence the efficiency of its interaction with mouse or human TLR4-MD2 and can include the number of lipid A acyl chains, acyl chain length, number and position of phosphate groups, and the presence of double bonds within the acyl chain structure [23]. MD2 contains two antiparallel beta-sheet domains which reconfigure into a large open pocket upon heterodimerization of TLR4-MD2. ...
... PA alone would not be sufficient to coordinate the molecular interactions of TLR4 and other membrane proteins to initiate the release of inflammatory cytokines from immune cells [35]. TLR4 action requires the coupling of a TLR4-MD2 membrane protein complex to form dimers and further interactions with other membrane proteins [36], so individual fatty acid chains would not suffice to accomplish this coupling [37]. Nevertheless, authors continue to indicate that SFA activates TLR4 to induce inflammatory changes [38,39]. ...
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Saturated fats are widely seen as undesirable components of a healthy diet, as a result of their illusory association with elevated serum cholesterol. The regulation of serum cholesterol is now better understood and a lack of polyunsaturated fatty acids, rather than an abundance of saturated fatty acids, is responsible. Palmitic acid was shown to incite inflammation at unnaturally high concentrations in tissue culture, but later was found to play an auxiliary role as a precursor to ceramide biosynthesis and possibly in the palmitoylation of membrane receptors involved in the initiation of inflammation. Studies of arthritic inflammation in lab animals showed that dietary saturated fats are anti-inflammatory, whereas polyunsaturated oils are pro-inflammatory. Inflammation plays a role in numerous metabolic diseases, including insulin resistance, fatty liver disease and metabolic syndrome, among others. Fat, as triglycerides in adipose tissue, is an efficient way for living organisms to store energy and reduce the toxicity of other macronutrients. Macronutrients, such as excess carbohydrates and polyunsaturated fatty acids, are converted to saturated and monounsaturated fatty acids for storage as triglycerides in adipose tissue. Fatty acids are released from adipose tissue during fasting and as a result of some metabolic disorders, where elevated levels of nonesterified fatty acids in blood can lead to hepatic lipid accumulation, inflammation and insulin resistance. Although most serum nonesterified fatty acids may be saturated fatty acids, they are not necessarily derived from the diet. This paper will attempt to clarify the role of saturated fatty acids, and palmitic acid in particular, with regard to certain adverse health conditions.
... In febrile dengue, monocytes, particularly those in the IM and CM subsets, presented increased TLR2 and TLR4 expression. TLR4, known for its role in bacterial responses, also contributes to dengue pathogenesis [49][50][51]. TLR2 activation triggers the NF-κB pathway by inducing the expression of proinflammatory cytokines, such as IL-1β and TNF-α, during DENV infection [49][50][51]. Studies have shown that elevated TLR2 expression in the CM and IM subsets correlates with disease severity, whereas low TLR expression in the NCM correlates with milder forms of dengue, indicating endothelial protection [52][53][54]. ...
... TLR4, known for its role in bacterial responses, also contributes to dengue pathogenesis [49][50][51]. TLR2 activation triggers the NF-κB pathway by inducing the expression of proinflammatory cytokines, such as IL-1β and TNF-α, during DENV infection [49][50][51]. Studies have shown that elevated TLR2 expression in the CM and IM subsets correlates with disease severity, whereas low TLR expression in the NCM correlates with milder forms of dengue, indicating endothelial protection [52][53][54]. ...
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Background: Dengue is a vector-borne debilitating disease that is manifested as mild dengue fever, dengue with warning signs, and severe dengue. Dengue infection provokes a collective immune response; in particular, the innate immune response plays a key role in primary infection and adaptive immunity during secondary infection. In this review, we comprehensively walk through the various markers of immune response against dengue pathogenesis and outcome. Main body: Innate immune response against dengue involves a collective response through the expression of proinflammatory cytokines, such as tumor necrosis factors (TNFs), interferons (IFNs), and interleukins (ILs), in addition to anti-inflammatory cytokines and toll-like receptors (TLRs) in modulating viral pathogenesis. Monocytes, dendritic cells (DCs), and mast cells are the primary innate immune cells initially infected by DENV. Such immune cells modulate the expression of various markers, which can influence disease severity by aiding virus entry and proinflammatory responses. Adaptive immune response is mainly aided by B and T lymphocytes, which stimulate the formation of germinal centers for plasmablast development and antibody production. Such antibodies are serotype-dependent and can aid in virus entry during secondary infection, mediated through a different serotype, such as in antibody-dependent enhancement (ADE), leading to DENV severity. The entire immunological repertoire is exhibited differently depending on the immune status of the individual. Short conclusion: Dengue fever through severe dengue proceeds along with the modulated expression of several immune markers. In particular, TLR2, TNF-α, IFN-I, IL-6, IL-8, IL-17 and IL-10, in addition to intermediate monocytes (CD14+CD16+) and Th17 (CD4+IL-17+) cells are highly expressed during severe dengue. Such markers could assist greatly in severity assessment, prompt diagnosis, and treatment.
... Lipid A is the bioactive anchor of LPS and functions as a potent ligand for Tolllike receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) receptor of the innate immune system stimulating the host immune responses [15,16]. This activation can then signal via two distinct pathways, the MyD88dependent and the Toll/IL-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent pathways, thereby influencing adaptive immune responses [17]. In the MyD88-dependent pathway, dimerization of TLR4/MD-2 activates the transcription factor NFκB triggering the release of pro-inflammatory cytokines [17]. ...
... This activation can then signal via two distinct pathways, the MyD88dependent and the Toll/IL-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent pathways, thereby influencing adaptive immune responses [17]. In the MyD88-dependent pathway, dimerization of TLR4/MD-2 activates the transcription factor NFκB triggering the release of pro-inflammatory cytokines [17]. Additionally, TLR4 can be internalized into endosomes activating the TRIF pathway, which ultimately results in the activation of the IRF3 transcription factor, the production of type I interferons and activation of dendritic cells, thereby, playing an important role in the stimulation of early T-cell responses [18,19]. ...
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Background Bordetella pertussis is the causative agent of whooping cough or pertussis. Although both acellular (aP) and whole-cell pertussis (wP) vaccines protect against disease, the wP vaccine, which is highly reactogenic, is better at preventing colonization and transmission. Reactogenicity is mainly attributed to the lipid A moiety of B. pertussis lipooligosaccharide (LOS). Within LOS, lipid A acts as a hydrophobic anchor, engaging with TLR4-MD2 on host immune cells to initiate both MyD88-dependent and TRIF-dependent pathways, thereby influencing adaptive immune responses. Lipid A variants, such as monophosphoryl lipid A (MPLA) can also act as adjuvants. Adjuvants may overcome the shortcomings of aP vaccines. Results This work used lipid A modifying enzymes from other bacteria to produce an MPLA-like adjuvant strain in B. pertussis. We created B. pertussis strains with distinct lipid A modifications, which were validated using MALDI-TOF. We engineered a hexa-acylated monophosphorylated lipid A that markedly decreased human TLR4 activation and activated the TRIF pathway. The modified lipooligosaccharide (LOS) promoted IRF3 phosphorylation and type I interferon production, similar to MPLA responses. We generated three other variants with increased adjuvanticity properties and reduced endotoxicity. Pyrogenicity studies using the Monocyte Activation Test (MAT) revealed that these four lipid A variants significantly decreased the IL-6, a marker for fever, response in peripheral blood mononuclear cells (PBMCs). Conclusion These findings pave the way for developing wP vaccines that are possibly less reactogenic and designing adaptable adjuvants for current vaccine formulations, advancing more effective immunization strategies against pertussis.
... Paradoxically, Douglass et al. recently showed that microglial inflammatory function during an HFD consumption enhances glucose physiological responses regardless of inducing adiposity (148) and preventing microglial IKKb signaling pathway in response to an HFD prevents obesity but impairs glucose tolerance (148). Furthermore, hypercaloric diets stimulate microglial TLR4, which responds to lipids (149,131), thus inducing TNFa secretion, inhibiting NPY/AgRP neuronal activity (150) and increasing POMC neuronal excitability (114,151). ...
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Microglia are highly dynamic cells that have been mainly studied under pathological conditions. The present review discusses the possible implication of microglia as modulators of neuronal electrical responses in physiological conditions and hypothesizes how these cells might modulate hypothalamic circuits in health and during obesity. Microglial cells studied under physiological conditions are highly diverse, depending on the developmental stage and brain region. The evidence also suggests that neuronal electrical activity modulates microglial motility to control neuronal excitability. Additionally, we show that the expression of genes associated with neuron-microglia interaction is down-regulated in obese mice compared to control-fed mice, suggesting an alteration in the contact-dependent mechanisms that sustain hypothalamic arcuate-median eminence neuronal function. We also discuss the possible implication of microglial-derived signals for the excitability of hypothalamic neurons during homeostasis and obesity. This review emphasizes the importance of studying the physiological interplay between microglia and neurons to maintain proper neuronal circuit function. It aims to elucidate how disruptions in the normal activities of microglia can adversely affect neuronal health.