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Mast cell, pro-inflammatory and anti-inflammatory: Jekyll and Hyde, the story continues
Abstract
IL-1 family members include inflammatory and anti-inflammatory cytokines. They can be beneficial or detrimental, not only in cancer, but also in inflammatory conditions. Mast cells (MCs) originate from CD34+/CD117+/CD13+ pluripotent hematopoietic stem cells, express c-Kit receptor (c-Kit-R), which regulates the proliferation and sustain the survival, differentiation and maturation of MCs. They are immune cells involved in innate and adaptive immunity, allergy, autoimmunity, cancer and inflammation. MCs along with T cells and macrophages release interleukin (IL)-10, which is a pleiotropic immunoregulatory cytokine with multiple biological effects. IL-10 inhibits Thl inflammatory cells, in particular TNF mostly generated by macrophages and MCs, and down-regulates IFN-γ, IL-1 and IL-6. IL-37 is a family member cytokine which binds IL-18 receptor a chain and inhibits inflammatory mediators including TNF, IL-1, IL-6, IL-33 and nitric oxide (NO). IL-37 similar to IL-10 inhibits MC inflammatory cytokines in several disorders, including asthma, allergy, arthrtitis, and cancer. Here we report a study comparing IL-10 with IL-37, two anti-inflammatory cytokines.
... Mast cells release members of the interleukin-1 (IL-1) cytokine family, which include both inflammatory and antiinflammatory cytokines [175]. Mast cells are recruited to injury and pain sties by the potent chemotactic mediator TGF-β [176]. ...
... Mast cells, similar to T lymphocytes and macrophages, release the anti-inflammatory cytokines IL-10 and TGF-β [195,196]. They act by inhibiting Th1 inflammatory cells, in particular, TNF, which is mostly generated by macrophages and mast cells, while also downregulating interferon-γ (IFN-γ), IL-1, and IL-6 [175] and by IL-10 promoting the degradation of cytokine mRNA, and TGF-beta primarily suppressing cytokine translation [70]. IL-37 is a family member cytokine which binds IL-18 receptor alpha chain and inhibits inflammatory mediators including TNF, IL-1, IL-6, IL-33, and NO. ...
... IL-37 is a family member cytokine which binds IL-18 receptor alpha chain and inhibits inflammatory mediators including TNF, IL-1, IL-6, IL-33, and NO. Similar to IL-10, IL-37 inhibits mast cell inflammatory cytokines [175]. Blocking IL-1 with IL-37 reduces symptoms of inflammatory diseases. ...
Injury typically results in the development of neuropathic pain, but the pain normally decreases and disappears in paralleled with wound healing. The pain results from cells resident at, and recruited to, the injury site releasing pro-inflammatory cytokines and other mediators leading to the development of pro-inflammatory environment and causing nociceptive neurons to develop chronic ectopic electrical activity, which underlies neuropathic pain. The pain decreases as some of the cells that induce pro-inflammation, changing their phenotype leading to the blocking the release of pro-inflammatory mediators while releasing anti-inflammatory mediators, and blocking nociceptive neuron chronic spontaneous electrical activity. Often, despite apparent wound healing, the neuropathic pain becomes chronic. This raises the question of how chronic pain can be eliminated. While many of the cells and mediators contributing to the development and maintenance of neuropathic pain are known, a better understanding is required of how the injury site environment can be controlled to permanently eliminate the pro-inflammatory environment and silence the chronically electrically active nociceptive neurons. This paper examines how methods that can promote the transition of the pro-inflammatory injury site to an anti-inflammatory state, by changing the composition of local cell types, modifying the activity of pro- and anti-inflammatory receptors, inducing the release of anti-inflammatory mediators, and silencing the chronically electrically active nociceptive neurons. It also examines the hypothesis that factors released from platelet-rich plasma applied to chronic pain sites can permanently eliminate chronic inflammation and its associated chronic pain.
... Mast cells have been described in the tumoral stroma and could play an important role in the angiogenesis switch during tumor growth [118,119]. They release a range of proangiogenic molecules, including VEGF, angiopoietin-1, heparin, TNF and FGF [99,120]. Association between mast cells and new vessel formation has been reported in many tumors, including breast cancer, colorectal cancer, pancreatic carcinoma, colorectal cancer and uterine cervix cancer [89,[120][121][122][123]. ...
... They release a range of proangiogenic molecules, including VEGF, angiopoietin-1, heparin, TNF and FGF [99,120]. Association between mast cells and new vessel formation has been reported in many tumors, including breast cancer, colorectal cancer, pancreatic carcinoma, colorectal cancer and uterine cervix cancer [89,[120][121][122][123]. Moreover, it has been shown that the number of tumor-infiltrating mast cells correlates with increased intratumoral microvessel density, enhanced tumor growth and tumor invasion, and poor clinical outcome [120,121]. ...
... Association between mast cells and new vessel formation has been reported in many tumors, including breast cancer, colorectal cancer, pancreatic carcinoma, colorectal cancer and uterine cervix cancer [89,[120][121][122][123]. Moreover, it has been shown that the number of tumor-infiltrating mast cells correlates with increased intratumoral microvessel density, enhanced tumor growth and tumor invasion, and poor clinical outcome [120,121]. ...
Background
In mammals, inflammation is required for wound repair and tumorigenesis. However, the events that lead to inflammation, particularly in non-healing wounds and cancer, are only partly understood.
Findings
Mast cells, due to their great plasticity, could orchestrate the inflammatory responses inducing the expression of extraembryonic programs of normal and pathological tissue formation. This heterogeneity of mast cells could allow a microenvironment to be recreated similar to the extraembryonic structures, i.e., amnion and yolk sac, which are needed for embryonic development. Mast cells could provide a framework for understanding the connection between inflammation and tumor growth, invasion and metastasis. In this way, the mast cells could express inflammatory phenotypes, which would enable the cancer stem cells to develop. Thus, the cancer cell uses mast cells to express the extraembryonic functions that are needed to allow the cancer stem cell to proliferate and invade. If so, then by using this appropriate inflammatory interstitial microenvironment, a cancer stem cell can reach maximum levels of growth and invasion inside the host.
Conclusion
Therefore, the comparison of tumors with wounds that do not heal would be supported since both pathological processes use extraembryonic mechanisms by mast cells. The adoption of these mechanisms warrants tumor survival in an embryonic-like state.
... In this review, the fundamental role of mast cells and sensory nerves in itch is discussed. Conti et al. (2017)], but they also contribute to carcinogenesis (Biswas et al., 2014;Hu et al., 2018;Saadalla et al., 2018). Mast cells are abundant in bodyenvironment interfaces in the skin and the gastrointestinal tract (Gurish and Austen, 2001) as well as present in the meninges of the central nervous system (Bo et al., 1992;Theoharides et al., 2005), and in the lung (Bradding et al., 2006). ...
The intimate interaction between mast cells and sensory nerves can be illustrated by the wheal and surrounding flare in an urticarial reaction in human skin. This reaction is typically associated with an intense itch at the reaction site. Upon activation, cutaneous mast cells release powerful mediators, such as histamine, tryptase, cytokines, and growth factors that can directly stimulate corresponding receptors on itch-mediating sensory nerves. These include, e.g., H1- and H4-receptors, protease-activated receptor-2, IL-31 receptor, and the high-affinity receptor of nerve growth factor (TrkA). On the other hand, sensory nerves can release neuropeptides, including substance P and vasoactive intestinal peptide, that are able to stimulate mast cells to release mediators leading to potentiation of the reciprocal interaction, inflammation, and itch. Even though mast cells are well recognized for their role in allergic skin whealing and urticaria, increasing evidence supports the reciprocal function between mast cells and sensory nerves in neurogenic inflammation in chronic skin diseases, such as psoriasis and atopic dermatitis, which are often characterized by distressing itch, and exacerbated by psychological stress. Increased morphological contacts between mast cells and sensory nerves in the lesional skin in psoriasis and atopic dermatitis as well as experimental models in mice and rats support the essential role for mast cell-sensory nerve communication in consequent pruritus. Therefore, we summarize here the present literature pointing to a close association between mast cells and sensory nerves in pruritic skin diseases as well as review the essential supporting findings on pruritic models in mice and rats.
... MCs can have a pro-inflammatory or an anti-inflammatory activity [20,21], but a polarization state, defined as a featured and alternative phenotype, is not currently recognized. A hypothetical anti-inflammatory phenotype for mast cell, indicated by "MC2" state, should be characterized by the production of IL-10; interleukin-10 notably inhibits Th1 cells activation and contribute to push on macrophages towards an M2 polarization state. ...
The data of literature are discordant about the role of mast cells in different types of neoplasms. In this paper the authors propose the hypothesis that tumor-associated mast cells may switch to different polarization states, conditioning the immunogenic capacities of the different neoplasms. Anti-inflammatory polarized mast cells should express cytokines such as interleukin-10 (IL-10) and then mast cells number should be inversely related to the intensity of inflammatory infiltrate. On the contrary, when mast cells do not express anti-inflammatory cytokines their number should be directly related to the intensity of the inflammatory infiltrate. In this paper we briefly argue around feasible approaches, based on the retrospective studies of tumor tissue samples from neoplasms considered "immunologically hot" and neoplasms considered "immunologically cold", through immunohistochemistry and immunofluorescence techniques (confocal microscopy). The establishment of the actual existence of a polarization interchange of mast cells, could lead to a new vision in prognostic terms, useful to contrive new approaches in immunotherapy of tumors.
... Also, it must be considered that future therapeutic intervention, targeting mast cell activity, hypothetically could provide another tool in this scenario. 5,9,10 Generally speaking, a possible future direction for research in the therapy of brain tumors could be the molecular and immunological targeting of the innate immune system. ...
Innate immunity plays a central role in neoplasms, including those affecting the central nervous system (CNS). Nowadays, tumors classification, especially that regarding gliomas, is based on molecular features such as mutations in isocitrate dehydrogenase (IDH) genes and the presence of co-deletion 1p/19q. Therapy, in most cases, is based on surgery, radiotherapy, and pharmacological treatment with chemotherapeutic agents such as temozolomide. However, the results of the treatments, after many decades, are not completely satisfactory. There is a class of drugs, used to treat cancer, which modulates immune response; in this class, the immune checkpoint inhibitors and vaccines play a prominent role. These drugs were evaluated for the treatment of gliomas, but they exhibited a poor outcome in clinical trials. Those scarce results could be due to the response of tumor-associated macrophage that creates imbalances between innate and adaptive immunity and changes in blood–brain barrier properties. Here, we have briefly reviewed the current literature on this topic, focusing on the possible role for innate immunity in the failure of immunotherapies against brain tumors.
... Therefore, MCs secrete inflammatory cytokines, including IL-1, IL-6 and TNF, which promote pain and thrombosis in migraine ( Conti et al., 2017). Augmentation of IL-1 in the brain contributes to behavioral al- terations, increased feelings of fatigue, depressed mood, fever, and pain in both animals and humans (Roerink et al., 2017). ...
Migraine is a common painful neurovascular disorder usually associated with several symptoms, such as photophobia, phonophobia, nausea, vomiting and inflammation, and involves immune cells. Mast cells (MCs) are immune cells derived from hematopoietic pluripotent stem cells which migrate and mature close to epithelial, blood vessels, and nerves. In almost all vascularized tissues there are MCs that produce, contain and release biologically active products including cytokines, arachidonic acid compounds, and proteases. In addition, MCs participate in innate and adaptive immune responses. Innate responses in the central nervous system (CNS) occur during neuroinflammatory phenomena, including migraine. Antigens found in the environment have a crucial role in inflammatory response, causing a broad range of diseases including migraine. They can be recognized by several innate immune cells, such as macrophages, microglia, dendritic cells and MCs, which can be activated trough Toll-like receptor (TLR) signaling. MCs reside close to primary nociceptive neurons, associate with nerves, and are capable of triggering local inflammation. MCs are involved in the pathophysiology of various tissues and organs, especially where there is an increase of angiogenesis. Activated MCs release preformed mediators include histamine, heparin, proteases (tryptase, chimase), hydrolases, cathepsin, carboxypeptidases, and peroxidase, and they also generate pro-inflammatory cytokines/chemokines. In addition, activated macrophages, microglia and MCs in the CNS release pro-inflammatory cytokines which provoke an increase of arachidonic acid product levels and lead to migraine and other neurological manifestations including fatigue, nausea, headaches and brain fog. Innate immunity and pro-inflammatory interleukin (IL)-1 cytokine family members can be inhibited by IL-37, a relatively new member of the IL-1 family. In this article, we report that some pro-inflammatory cytokines inducing migraine may be inhibited by IL-37, a natural suppressor of inflammation, and innate and acquired immunity.
Background:
Neuroinflammation is implicated in cerebral vasospasm and brain injuries after subarachnoid hemorrhage (SAH). In addition to classical neuroinflammation with increased inflammatory cytokines, a sterile neurogenic inflammation characterized by release of potent vasoactive neuropeptides may be responsible for brain injuries after SAH. Sympathetic discharges from superior cervical ganglion contribute to vasoconstriction of cerebral arteries Thus, we investigated the effects of surgical cervical sympathectomy on the neurogenic inflammatory neuropeptides shortly after SAH induction in a model of SAH in rats.
Methods:
Male Wistar rats were divided into 4 groups: control; was not touched, saline group; 300 μl of saline was injected into prechiasmatic cistern, SAH+Sham group; 300 μl of autologous blood was injected to induce subarachnoid hemorrhage into prechiasmatic cistern; SAH+Symp group; the left cervical sympathetic branch was surgically removed after the induction of SAH. Levels of neuropeptides CGRP, SP and VIP which are responsible for neurogenic inflammation, in plasma, trigeminal ganglion, brainstem and brain tissue were measured by ELISA. In addition, c-fos expression as a marker of neuronal activation in the trigeminal nucleus caudalis (TNC) was determined by immunohistochemical staining.
Results:
SAH significantly increased c-fos expression in the TNC, as well as CGRP, SP and VIP concentrations in plasma and trigeminal ganglion neurons, and also CGRP and SP concentrations in the brainstem. Cervical sympathectomy application significantly reduced the increases in these parameters induced by SAH.
Conclusions:
Our findings suggest that cervical sympathectomy treatment may prevent early brain injury by modulating SAH-induced neurogenic inflammatory neuropeptides such as CGRP, SP and VIP, and improve the quality of life in survivors following SAH.
Autism Spectrum Disorder (ASD) is a developmental condition characterized by impaired communication and obsessive behavior that affects 1 in 59 children. ASD is expected to affect 1 in about 40 children by 2020, but there is still no distinct pathogenesis or effective treatments. Prenatal stress has been associated with higher risk of developing ASD in the offspring. Moreover, children with ASD cannot handle anxiety and respond disproportionately even to otherwise benign triggers. Stress and environmental stimuli trigger the unique immune cells, mast cells, which could then trigger microglia leading to abnormal synaptic pruning and dysfunctional neuronal connectivity. This process could alter the “fear threshold” in the amygdala and lead to an exaggerated “fight-or-flight” reaction. The combination of corticotropin-releasing hormone (CRH), secreted under stress, together with environmental stimuli could be major contributors to the pathogenesis of ASD. Recognizing these associations and preventing stimulation of mast cells and/or microglia could greatly benefit ASD patients.
Purpose:
To review evidence of hypersensitivity reactions to allergens and/or pathogens transmitted via intimate contact.
Methods:
We reviewed PubMed for publications in English between 1980 and 2018 using the terms allergy, drugs, foods, hypersensitivity, intercourse, kissing, Kounis syndrome, mast cells, and semen.
Findings:
In human RELATIONSHIPS, intimate contact can occasionally have disastrous or even fatal consequences because antigens and pathogens can be transmitted via the oral and vaginal mucosa. Hypersensitivity to semen is an underrecognized problem. Some individuals also developed acute coronary hypersensitivity, which mimics myocardial infarction, known as Kounis syndrome.
Implications:
Hypersensitivity reactions to allergens and/or pathogens via intimate contact are common and should be recognized. Sensitive patients should be evaluated for atopic diathesis because such patients may be more susceptible and could also develop Kounis syndrome.
Introduction: An increasing number of patients present with multiple symptoms affecting many organs including the brain due to multiple mediators released by mast cells. These unique tissue immune cells are critical for allergic reactions triggered by IgE, but are also stimulated (not activated) by immune, drug, environmental, food, infectious, and stress triggers, leading to secretion of multiple mediators often without histamine and tryptase. The presentation, diagnosis and management of the spectrum of mast cell disorders is very confusing. As a result, specialists have recently excluded neuropsychiatric symptoms, and made the diagnostic criteria stricter, at the expense of excluding most patients.
Areas covered: A literature search was performed on papers published between January 1990 and November 2018 using MEDLINE. Terms used were activation, antihistamines, atopy, autism, brain fog, heparin, KIT mutation, IgE, inflammation, IL-6, IL-31, IL-37, luteolin, mast cells, mastocytosis, mediators, myalgic encephalomyelitis/chronic fatigue syndrome, mycotoxins, release, secretion, tetramethoxyluteolin, tryptase.
Expert commentary: Conditions associated with elevated serum or urine levels of any mast cell mediator, in the absence of any comorbidity that could otherwise explain such increases, should be considered mast cell activation disorders, or better yet be collectively termed “Mast Cell Mediator Disorders (MCMD)”. Emphasis should be placed on the identification of unique mast cell mediators, and development of drugs or supplements that inhibit their release.
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