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Mast cell; Inflammation; Neuropeptide; Cytokines; Immunity; Tumor; Allergy

Introduction

Mast cells (MCs) are derived from myeloid progenitor cells and upon maturation migrate to tissues where they carry out a variety of biological responses, including innate and adaptive immunity. Furthermore, MCs are immune cells involved in various diseases, including inflammatory, autoimmune, and allergic diseases [1]. MC maturation has been reported to occur in vitro and in vivo in the presence of stem cell factor (SCF), IL-3, IL-4, and IL-9. MCs are ubiquitous in the human body, but are primarily localized to the perivascular tissues and the central nervous system, the ‘CNS’ [2]. Located in corticotropin-releasing hormone (CRH)-positive neurons. The meninges also have MCs that are activated by vascular permeability-mediated stress and toxins. This is an effect not seen in MC-deficient rodents. Anti-inflammatory cytokines have shown good results both in vitro and in rodents, raising hopes for new therapeutics. However, due to the current lack of data on human clinical therapy, the dosage, efficacy, duration, and side effects of these cytokines are unknown and require further investigation to clarify. Antigens such as mutants of KIT show promise and are still under investigation, but no satisfactory studies on inhibition of proinflammatory cytokines have yet been reported. The purpose of this article is to describe the current knowledge on the interactions between MCs and Neuromodulators and the role of pro- and anti-inflammatory cytokines [3].

Mast cells and inflammation

Human MCs were first described by Paul Ehrlich, and about 100 years ago, Gilchrist observed that the number of MCs increases near blood vessels. Henry Dale in 1910 and Thomas Lewis in 1924 confirmed these results and reported that MC releases histamine to induce a wheal response and inflammation [4]. The exponential growth in the number of articles on MCs over the past decade reflects research interest in this intriguing immune cell. MCs are myeloid cells derived from CD34+/CD117+/CD13+ myeloid cells that mature into tissues under stimulation of growth factors such as SCF. MCs are classical cells for allergic diseases, but they can also mediate angiogenesis, acute and chronic inflammation, autoimmune diseases, tissue repair, neurological diseases and tumors. binding to SCF by exerting biological responses.

c-kit/CD117 is a proto-oncogene transmembrane tyrosine kinase receptor that has been immunolocalized on a variety of cells, including MCs. CD117 is a 145 Kd glycoprotein that is the product of the Kit gene, SCF is a c-Kit ligand termed MC growth factor, and c-Kit receptor autophosphorylation is key to MC-mediated survival signaling. In addition, CD117 is diagnostic of some tumors, such as MC-rich gastrointestinal tumors. Experiments in mice have shown that c-kit is encoded at a mouse locus that affects immature germ cells. However, for ethical and practical reasons, there are not many studies on human MCs in vivo, with the most important results on this topic coming from rodent studies. Indeed, the biological effects of MC have been studied in MC-deficient mice such as KitW-f/KitW-f, KitW/KitW-v, and KitW-sh/ KitW-sh with C-Kit receptor dysfunction [5].

Neuromodulators

A recent study examining the effects of neuromodulators on inflammatory diseases reported that they can stimulate immune cells, including MCs, to produce proinflammatory cytokines that can exacerbate inflammatory diseases. In this article, investigation of cytokine inhibition by IL-37 or IL-38, suppressors of IL-1, is a novel strategy for acute and chronic diseases caused by elevated levels of neuromodulators such as substance P, CRH and neurotensin. is. Therefore, as many inflammatory neurological diseases are incurable, the current literature on neuropeptide-induced inflammation needs additional information to describe new therapeutic strategies [6].

SP was discovered by von Euler in his 1931 and characterized by Riemann and Chan in 1970. It is a highly conserved neuropeptide isolated from rat brain, secreted primarily by neurons and involved in nociception, hypotonia, muscle contraction, and inflammation. Numerous studies have confirmed the proinflammatory effects of SP acting through specific neurokinin-1 (NK-1) [7].

SP is a member of the tachykinin peptide hormone family, located on human chromosome 7 and encoded by the TAC1 gene. SP activates MCs through specific receptors without degranulation and induces granulocytic infiltration through the synthesis of multiple cytokines, including TNF and IL-8. In addition, neuromodulators activate nerve growth factor (NGF) and NTMC and can participate in inflammatory processes. Indeed, in some neurological diseases, MC activation increases vascular permeability and subsequently activates NK1 receptors [8].

Corticotropin-releasing hormone

Harris reported in 1948 that the hypothalamus is an important link between the nervous and endocrine systems. Information is generated from the nucleus of the hypothalamus directly to the locus coeruleus, the major center of norepinephrine release, and from there to the efferent pathway that leads directly to the adrenal medulla and causes the release of catecholamines, including adrenaline, norepinephrine, and dopamine. is generated. .to start. Catecholamines may interact with proinflammatory cytokines secreted after cognitive (stress) or non-cognitive (microbial) stimulation. Circulating cytokines reach the CNS and exert inflammatory effects by binding to their receptors. CRH acts through two receptors, corticotropin-releasing hormone receptor (CRHR)-1 and CRHR-2, and is subdivided into CRHR-2α and CRHR- 2β. He isolated and characterized his CRH from the hypothalamus of sheep. It closely resembles the human peptide and is commonly expressed in the brain [9]. The hypothalamus he secretes CRH, the pituitary gland secretes adrenocorticotropic hormone (ACTH), and at the adrenal cortical level the anti-inflammatory marker cortisol. Cortisol and catecholamines produced by the adrenal gland reduce inflammation by inhibiting pro-inflammatory cytokines such as IL-1, TNF and IL. Small cell neurons of the paraventricular nucleus are the major source of CRH in rats and humans. This hormone is secreted and transported to the anterior pituitary gland.

In humans, CRH is also found outside the CNS, including in the adrenal medulla, stomach, placenta, pancreas, duodenum, and some tumors. Administration of CRH in vivo causes elevation of plasma ACTH and cortisol with dose-dependent side effects. Thus, upon antigenic stimulation, CRH is secreted from the hypothalamus and activates the hypothalamic-pituitary-adrenal (HPA) axis, but is also released from neurons outside the CNS and generated by immune cells, including MCs [10].

Neurotensin

In 1973, Susan Lehman (now the group’s principal investigator) isolated NT for the first time. NT is a 13 amino acid peptide with roles as a neuromodulator and neurotransmitter in the CNS. There are four cellular receptors that bind NT. NTSR 1, NTSR2, and the type 1 receptors Sortilin 1 (Sort 1) and SorLA. NTSR1, which has high neuron affinity, and NTSR2, which has low activity, were the first to be discovered and are therefore the most studied. NTSR1 is more highly expressed in neurons and NTSR2 is weakly expressed, but these data have not yet been confirmed. NT regulates the gastrointestinal and cardiovascular system and is a mediator of neurological responses such as pain, psychosis, thermoregulation, ethanol sensitivity and analgesia. Several studies have shown that NT can act as an antipsychoticinduced dopaminergic agent against schizophrenia without affecting NTS1 modification. It has also been observed that low NT levels in the thalamus promote more alcohol consumption.

Conclusions

Future use of anti-inflammatory cytokines may replace or be administered in combination with corticosteroid use, which reduces inflammation and causes serious side effects such as immunosuppression. In this article, we investigated the role of neuropeptide substance P, CRH, and neurotensin in cytokine MC activation. reported that these neuromodulators stimulate IL-1, IL-6, and TNF. Inhibition of IL-1 by IL-37 or IL-38 may open new therapeutic avenues and is a novel concept not yet described in the MC literature. MCs coexist with IL- 1-producing macrophages, lymphocytes, endothelial cells, and other inflammatory cells. This cytokine exerts autocrine effects by inducing other pro-inflammatory cytokines such as TNF and stimulating itself.

This effect triggers a cytokine storm with a dramatic inflammatory response. Inhibiting IL-1 with IL-37 or IL-38 could be a new therapeutic strategy. However, IL-37 and IL-38 have only been used in research and are not yet therapeutically available. Therefore, certain points should be clarified before using these inhibitory cytokines, such Concentrations used in humans, possible side effects, immunosuppression and lethality from in vivo treatment.

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