Impact of TNF and IL-33 Cytokines on Mast Cells in Neuroinflammation.

Mast cells (MCs) are derived from hematopoietic progenitors, mature in vascularized tissues, and participate in innate and acquired immunity. Neuroinflammation is a highly debated topic in the biomedical literature; however, the impact of tumor necrosis factor (TNF) and IL-33 on MCs in the brain has not been widely addressed. MCs can be activated by IgE binding to FcεRI, as well as by different antigens. After activation, MCs mediate various immunological and inflammatory responses through TNF and IL-33. TNF has two receptors: TNFR1, a p55 molecule, and TNFR2, a p75 molecule. This cytokine is the only one of its kind to be stored in the granules of MCs and can also be generated by de novo synthesis via mRNA. In the central nervous system (CNS), TNF is produced almost exclusively by microglial cells, neurons, astrocytes, and, minimally, by endothelial cells. After its release into brain tissue, TNF rapidly induces the adhesion molecules endothelial leukocyte adhesion molecule 1 (ELAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) in endothelial cells. TNF causes the chemoattraction of neutrophils by inducing several molecules, including CXC chemokines (IL-8). Both MCs and microglial cells act as a primary barrier against foreign molecules in the CNS, producing pro-inflammatory cytokines such as IL-33. IL-33 belongs to the IL-1 family, is activated through the ST2L/IL1-RAcP receptor complex, and mediates both the innate and adaptive immune response. IL-33 is a nuclear transcription factor expressed in the brain, where it induces pro-inflammatory cytokines (TNF and IL-1) and chemokines (CCL2, CCL3, CCL5, and CXCL10). Therefore, MCs and microglia in the CNS are a source of pro-inflammatory cytokines, including TNF and IL-33, that mediate many brain diseases. The inhibition of TNF and IL-33 may represent a new therapeutic approach that could complement existing neuroinflammatory therapies.

Activation of Mast Cells by Neuropeptides: The Role of Pro-Inflammatory and Anti-Inflammatory Cytokines.

Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in the scientific literature; it is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptide substance P (SP), corticotropin-releasing hormone (CRH), and neurotensin, and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.

Mast Cell Cytokines in Acute and Chronic Gingival Tissue Inflammation: Role of IL-33 and IL-37.

Much evidence suggests autoimmunity in the etiopathogenesis of periodontal disease. In fact, in periodontitis, there is antibody production against collagen, DNA, and IgG, as well as increased IgA expression, T cell dysfunction, high expression of class II MHC molecules on the surface of gingival epithelial cells in inflamed tissues, activation of NK cells, and the generation of antibodies against the azurophil granules of polymorphonuclear leukocytes. In general, direct activation of autoreactive immune cells and production of TNF can activate neutrophils to release pro-inflammatory enzymes with tissue damage in the gingiva. Gingival inflammation and, in the most serious cases, periodontitis, are mainly due to the dysbiosis of the commensal oral microbiota that triggers the immune system. This inflammatory pathological state can affect the periodontal ligament, bone, and the entire gingival tissue. Oral tolerance can be abrogated by some cytokines produced by epithelial cells and activated immune cells, including mast cells (MCs). Periodontal cells and inflammatory-immune cells, including mast cells (MCs), produce cytokines and chemokines, mediating local inflammation of the gingival, along with destruction of the periodontal ligament and alveolar bone. Immune-cell activation and recruitment can be induced by inflammatory cytokines, such as IL-1, TNF, IL-33, and bacterial products, including lipopolysaccharide (LPS). IL-1 and IL-33 are pleiotropic cytokines from members of the IL-1 family, which mediate inflammation of MCs and contribute to many key features of periodontitis and other inflammatory disorders. IL-33 activates several immune cells, including lymphocytes, Th2 cells, and MCs in both innate and acquired immunological diseases. The classic therapies for periodontitis include non-surgical periodontal treatment, surgery, antibiotics, anti-inflammatory drugs, and surgery, which have been only partially effective. Recently, a natural cytokine, IL-37, a member of the IL-1 family and a suppressor of IL-1b, has received considerable attention for the treatment of inflammatory diseases. In this article, we report that IL-37 may be an important and effective therapeutic cytokine that may inhibit periodontal inflammation. The purpose of this paper is to study the relationship between MCs, IL-1, IL-33, and IL-37 inhibition in acute and chronic inflamed gingival tissue.

State of art in intra-articular hip injections of different medications for osteoarthritis: a systematic review.

BACKGROUND: Intra-articular hip injections for osteoarthritis represent a useful instrument to reduce pain and disability in the common clinical practice. Several medications can be injected locally with different level of evidence-based efficacy. OBJECTIVE: The objective of this systematic review is to investigate the effectiveness of intra-articular injections of different medications or substances for the pain treatment and the management of disability in subjects affected by hip osteoarthritis. METHODS: Two reviewers selected independently randomised controlled trials published in the last 10 years, using PubMed and Scopus databases. The risk of bias was evaluated with Cochrane library assessment tool. RESULTS: 12 randomised controlled trials have been selected. We found 8 papers comparing hyaluronic acid with platelet rich plasma, with corticosteroids and with saline solution; 1 paper compares two types of hyaluronic acid with different molecular weights; 3 papers study the effects of corticosteroids alone or compared to ketorolac or saline solution. CONCLUSIONS: The studies reviewed were heterogeneous regarding sample size, level of osteoarthritis, evaluated with Kellegren-Lawrence score, medications used and follow up timings. However, we have observed that intra-articular injections of platelet-rich plasma seem to decrease pain at short term and disability at long term, in patients affected by hip osteoarthritis better than hyaluronic acid. The association of hyaluronic acid and corticosteroids could give better results compared to hyaluronic acid alone, while the use of intra-articular ketorolac and saline solution requires more studies.

Mast Cell Cytokines IL-1, IL-33, and IL-36 Mediate Skin Inflammation in Psoriasis: A Novel Therapeutic Approach with the Anti-Inflammatory Cytokines IL-37, IL-38, and IL-1Ra.

Psoriasis (PS) is a skin disease with autoimmune features mediated by immune cells, which typically presents inflammatory erythematous plaques, and is associated with many comorbidities. PS exhibits excessive keratinocyte proliferation, and a high number of immune cells, including macrophages, neutrophils, Th1 and Th17 lymphocytes, and mast cells (MCs). MCs are of hematopoietic origin, derived from bone marrow cells, which migrate, mature, and reside in vascularized tissues. They can be activated by antigen-provoking overexpression of proinflammatory cytokines, and release a number of mediators including interleukin (IL)-1 and IL-33. IL-1, released by activated keratinocytes and MCs, stimulates skin macrophages to release IL-36-a powerful proinflammatory IL-1 family member. IL-36 mediates both innate and adaptive immunity, including chronic proinflammatory diseases such as psoriasis. Suppression of IL-36 could result in a dramatic improvement in the treatment of psoriasis. IL-36 is inhibited by IL-36Ra, which binds to IL-36 receptor ligands, but suppression can also occur by binding IL-38 to the IL-36 receptor (IL-36R). IL-38 specifically binds only to IL-36R, and inhibits human mononuclear cells stimulated with IL-36 in vitro, sharing the effect with IL-36Ra. Here, we report that inflammation in psoriasis is mediated by IL-1 generated by MCs-a process that activates macrophages to secrete proinflammatory IL-36 inhibited by IL-38. IL-37 belongs to the IL-1 family, and broadly suppresses innate inflammation via IL-1 inhibition. IL-37, in murine models of inflammatory arthritis, causes the suppression of joint inflammation through the inhibition of IL-1. Therefore, it is pertinent to think that IL-37 can play an inhibitory role in inflammatory psoriasis. In this article, we confirm that IL-38 and IL-37 cytokines emerge as inhibitors of inflammation in psoriasis, and hold promise as an innovative therapeutic tool.

Mast Cells Mediate Rheumatoid Arthritis-Inhibitory Role of IL-37.

Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory, disabling arthropathy that severely affects the quality of life. This disease involves several proinflammatory cytokines, including interleukin (IL)-1ß and tumor necrosis factor (TNF). IL-1 induces TNF and vice versa, causing joint damage and cartilage degradation. Current antirheumatic drugs may be effective, but they possess many unwanted side effects. In recent years, inhibitors of proinflammatory cytokines have increasingly entered mainstream clinical practice. Recent evidence indicates that IL-37, which has anti-inflammatory properties, is increased in the serum and is released from white blood cells in patients with RA. Mast cells (MCs), stimulated by the neuropeptide substance P (SP) and IL-33, release IL-1ß and TNF. Recent evidence indicates that large amounts of IL-1ß and TNF can be released from human MCs, which also secrete CXCL8, which promotes migration of immune cells, causing erosion of the bone and cartilage. Treatment with IL-37 can block the MC stimulation and release of inflammatory compounds, attenuating the severity of the disease and/or altering its progression.

Impact of mast cells in fibromyalgia and low-grade chronic inflammation: Can IL-37 play a role?

Fibromyalgia (FM) is a disease characterized by chronic widespread pain, fatigue, aches, joint stiffness, depression, cognitive dysfunction, and nonrestorative sleep. In FM, neurotransmission and glial activation can occur with an increase in inflammatory cytokines and involvement of mast cells (MCs) in the skin. FM skin biopsies show an increase in the number of MCs, as well as the production of corticotropin releasing hormone and substance P (SP) by the neurons, which in turn activate MCs to release neurosensitizing proinflammatory substances, such as cytokines, secreted preformed mediators, and lipids, which can exacerbate low-grade inflammation. In fact, certain proinflammatory cytokines are higher in FM and mediate muscle pain, the mechanism of which is not yet clear. MC-derived tumor necrosis factor (TNF) induces nerve growth factor (NGF) and participates in nerve fiber elongation in skin hypersensitivity. IL-37 is an inhibitor of proinflammatory IL-1 family members, which are generated and released by MCs. The goal of this article is to demonstrate that inflammatory cytokines and MC products play a role in FM and that inflammation may be inhibited by IL-37. Here, we propose IL-37 as a cytokine that contributes to improve the pathogenesis of FM by blocking IL-1 family members.

Mesotherapy: From Historical Notes to Scientific Evidence and Future Prospects.

Intradermal therapy, known as mesotherapy, is a technique used to inject a drug into the surface layer of the skin. In particular, it involves the use of a short needle to deposit the drug in the dermis. The intradermal microdeposit modulates the drug's kinetics, slowing absorption and prolonging the local mechanism of action. It is successfully applied in the treatment of some forms of localized pain syndromes and other local clinical conditions. It could be suggested when a systemic drug-sparing effect is useful, when other therapies have failed (or cannot be used), and when it can synergize with other pharmacological or nonpharmacological therapies. Despite the lack of randomized clinical trials in some fields of application, a general consensus is also reached in nonpharmacological mechanism of action, the technique execution modalities, the scientific rationale to apply it in some indications, and the usefulness of the informed consent. The Italian Mesotherapy Society proposes this position paper to apply intradermal therapy based on scientific evidence and no longer on personal bias.

Advances in Mast Cell Activation by IL-1 and IL-33 in Sjögren's Syndrome: Promising Inhibitory Effect of IL-37.

Sjögren's syndrome (SS) is a chronic autoimmune inflammatory disease that affects primarily older women and is characterized by irreversible damage of the exocrine glands, including tear (xerophthalmia) and salivary glands (xerostomia). Secretory glands lose their functionality due to the infiltration of immune cells, which produce cytokines and cause inflammation. Primary SS is characterized by dry syndrome with or without systemic commitment in the absence of other pathologies. Secondary SS is accompanied by other autoimmune diseases with high activation of B lymphocytes and the production of autoantibodies, including the rheumatoid factor. Other cells, such as CD4+ T cells and mast cells (MCs), participate in SS inflammation. MCs are ubiquitous, but are primarily located close to blood vessels and nerves and can be activated early in autoimmune diseases to express a wide variety of cytokines and chemokines. In the SS acute phase, MCs react by generating chemical mediators of inflammation, tumor necrosis factor (TNF), and other pro-inflammatory cytokines such as interleukin (IL)-1 and IL-33. IL-33 is the specific ligand for ST2 capable of inducing some adaptive immunity TH2 cytokines but also has pro-inflammatory properties. IL-33 causes impressive pathological changes and inflammatory cell infiltration. IL-1 family members can have paracrine and autocrine effects by exacerbating autoimmune inflammation. IL-37 is an IL-1 family cytokine that binds IL-18Rα receptor and/or Toll-like Receptor (TLR)4, exerting an anti-inflammatory action. IL-37 is a natural inhibitor of innate and acquired immunity, and the level is abnormal in patients with autoimmune disorders. After TLR ligand activation, IL-37 mRNA is generated in the cytoplasm, with the production of pro-IL-37 and later mature IL-37 caspase-1 mediated; both precursor and mature IL-37 are biologically active. Here, we discuss, for the first time, the current knowledge of IL-37 in autoimmune disease SS and propose a new therapeutic role.

Activation of mast cells mediates inflammatory response in psoriasis: Potential new therapeutic approach with IL-37.

Psoriasis (PS) is an autoimmune disorder characterized by chronic inflammatory skin immune-mediated disease which occurs in 2-4% of the worldwide population. PS is associated with an increased risk of cardiovascular disease and depression, and 30% of PS patients are affected with psoriatic arthritis. PS presents excessive keratinocyte proliferation, abnormal differentiation, and elevated mast cell (MC) number. In PS, there are enhanced type I interferon (IFN), angiogenesis, and over-expression of several proinflammatory cytokines, such as tumor necrosis factor and interleukin (IL)-1 family members generated by several immune cells including MCs. MCs are hematopoietic cells that reside in vascularized tissues, which, upon appropriate activation, release proinflammatory cytokines, an effect worsened by acute stress and PS. In recent years, IL-37 emerged as an anti-inflammatory cytokine which binds to alpha chain of the IL-18 receptor alpha (IL-18Rα) and downregulates MyD88. This effect leads to the inhibition of nuclear factor-κB (NF-κB) and mitogen activation protein kinase, with the suppression of inflammatory response. These observations candidate IL-37 as a potential new therapeutic cytokine for inflammatory disorders including PS.

Recent progress on pathophysiology, inflammation and defense mechanism of mast cells against invading microbes: inhibitory effect of IL-37.

Mast cells (MCs) have historically been considered masters of allergy, but there is substantial evidence supporting their contribution to tissue microorganism clearance. Their activation through the cross-linking of bound IgE provokes mast cell degranulation and activates tyrosine kinase (Syk and Lyn), leading to cytokine/chemokine generation and release. Current consensus holds that mast cells participate in the body's defense against numerous pathogens, including bacteria, fungi, viruses and parasites, but also contribute to the inflammatory response induced by these biological agents. In the light of the latest findings, we describe the cross-talk between mast cells and pathogenic microorganisms. This review summarizes our current understanding of the host immune response, with emphasis on the roles of MCs and the cytokine/chemokine network in provoking inflammation and generating protective immunity. This review addresses the ability of microorganisms to activate MCs provoking inflammation. We describe some MC-specific biological activities related to infections and discuss the evidence of MC mechanisms involved in the microbial activation which cause cytokine/chemokine generation-mediated inflammation, and provide a description of novel functions of mast cells during microbial infection. Interleukin (IL)-37 binds the α chain of the IL-18 receptor and suppresses MyD88-mediated inflammatory responses. IL-37 plays a pathological role in certain infections by inhibiting the production of pro-inflammatory cytokines, such as IL-1 and TNF. Here we report the interrelationship between IL-37, inflammatory cytokines and mast cells. Our report offers opportunities for the design of new therapeutic interventions in inflamed tissue induced by microorganism infections, acting on manipulation of mast cells and/or inflammatory cytokine blockage.

Current statement about Dry Needling practice in Italy after the opinion of the Italian Superior Health Council: practical implications for the safeguard of the patients in a case of malpractice.

In an our previous article, we described a case of a professional swimmer who presented a pneumothorax after treatment with dry needling (DN), performed by a physiotherapist. Although only few cases of serious adverse events after this treatment are reported in literature, the description of this case seemed to us of considerable interest to underline and discuss the medical-legal and ethical aspects regarding the skills and responsibilities of medical doctors and physiotherapists performing the procedure. The doctor-patient relationship, in this case, has failed because the patient has not received a correct diagnosis and adequate rehabilitation treatment according to international guidelines. In Italy a specialist medical doctor's prescription is required as a guide in the rehabilitation program performed by the physiotherapist after a clear and official diagnosis. The Italian Council of Health in the session of 13 June 2017, established that the practice of DN is a doctor's exclusive competence due to the invasive characteristics and potential complications of this technique.

Medico-Legal aspects of an unusual complication from an ear swab test: was the procedure necessary?

A 65-year-old woman affected by chronic pruritus in both ears was referred by her family physician to a private laboratory to undergo an ear swab test for microbiological and cultural examination. During the procedure on the right side, the patient experienced sudden pain, immediately followed by auricular fullness and dizziness. The clinician performing the swab did not perform an otoscopy and did not administer any topical or general medications. A few days later, purulent discharge appeared. Follow-up showed tympanic membrane perforation and mixed severe hearing loss. Indications for ear swab tests are currently unclear, and complications deriving from this apparently simple procedure are seldom reported.

Mast cells participate in allograft rejection: can IL-37 play an inhibitory role?

OBJECTIVE: The aim of this study was to evaluate the role of mast cells (MCs) in allograft rejection, eventually inhibited by IL-37. Immune cells including MCs participate in allograft rejection by generating IL-1, IL-33, TNF and other cytokines. METHODS: We evaluated allograft rejection on the experience of our experimental data and using the relevant literature. RESULTS: MCs are involved in initiation and regulation of innate and adaptive immune responses-pathways. MCs are important pro-inflammatory cells which express high-affinity receptor FceRI and can be activated by IgE and some pro-inflammatory cytokines, such as IL-1 and IL-33. The cross-linkage of high affinity IgE receptor on MCs by antigen ligation has a crucial role in allergy, asthma, anaphylaxis, cancer and allograft rejection. MCs mediate immunity in organ transplant, leading to the activation of allospecific T cells implicated in the rejection and generate pro-inflammatory cytokines/chemokines. IL-1 pro-inflammatory cytokine family members released by MCs mediate allograft rejection and inflammation. IL-37 is also an IL-1 family member generated by macrophage cell line in small amounts, which binds to IL-18Rα and produces an anti-inflammatory effect. IL-37 provokes the inhibition of TLR signaling, TLR-induced mTOR and (MyD88)-mediated responses, suppressing pro-inflammatory IL-1 family members and increasing IL-10. CONCLUSION: IL-37 inhibition offers the opportunity to immunologically modulate MCs, by suppressing their production of IL-1 family members and reducing the risk of allograft rejection, resulting as a potential good therapeutic new cytokine. Here, we report the relationship between inflammatory MCs, allograft rejection and pro-inflammatory and anti-inflammatory IL-37.

Impact of polyphenols on mast cells with special emphasis on the effect of quercetin and luteolin.

Polyphenols are ubiquitous in food and have long been recognized to possess antioxidant, anti-inflammatory and anticancer activities. Mast cells (MCs) are implicated in the pathogenesis of inflammatory diseases, allergy, autoimmunity and cancer. MCs derive from hematopoietic progenitor cells, reside virtually in all vascularized tissue and are activated by crosslinking of FceRI-bound IgE (at very high affinity: 1 × 1010 M-1) with multivalent antigen. MCs in cytoplasmic granules release preformed chemical mediators, and also they can release lipid mediators and cytokines/chemokines without degranulation. Luteolin, 3',4',5,7-tetrahydroxyflavone, is a flavonoid contained in many kinds of plants including vegetables and fruits. This anti-oxidant product inhibits interleukin (IL)-6, IL-8 and vascular endothelial growth factor (VEGF) production from tumor necrosis factor (TNF)-triggered keratinocytes, and is a candidate for use in alternative therapies in the treatment of inflammatory skin disorders. Quercetin (3,3',4',5,7-pentahydroxyflavone) is a ubiquitous flavonoid which exhibits anti-cancer, anti-oxidative and anti-inflammatory properties and causes a reduction in the availability of nitrite that influences vascular function. Quercetin exerts physiological functions though the interaction with phosphatidylinositol-3-phosphate kinase (PI3K), mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase (ERK), kinase (MEK) 1, and others, and has a negative effect on FceRI cross-linking and other activating receptors on mast cells. In this article we report for the first time the interrelationship between mast cells and polyphenols.

[Mesotherapy as a treatment of pain and disability in patients affected by neck pain in spondylartrosis]. / La mesoterapia come trattamento del dolore e della disabilità in pazienti affetti da cervicalgia in spondilartrosi.

Mesotherapy is a technique that treats locoregional pain with intradermal injection of a drug in the affected area. Its short-term efficacy was observed in patients with low back pain using both normal saline solution, if there were contraindications to drugs' use, or a cocktail of drugs (normal saline solution, lidocaine hydrochloride, and lysine acetylsalicylate), whereas only the latter provided benefit for up to three months after treatment. The aim of this study was to measure the effects of mesotherapy in patients affected by neck pain in spondylarthrosis, a common pathology in rehabilitation, associated with significant disability and increased health expenditure. One hundred patients participated in the study, of whom 50 (mean age 66.9 years) were treated with mesotherapy with a cocktail of drugs and 50 (mean age 64.7 years) with normal saline solution. Pain and disability were measured at different times (i.e. before treatment, at the end of five weeks of treatment, four weeks and 12 weeks after treatment), by using different pain scales, including a visual analogue scale, the short-form McGill pain questionnaire, the Present Pain Intensity scale and the Neck Disability Index. Mesotherapy with either normal saline solution or with a cocktail of drugs were both found to be effective in the short term in reducing pain and disability. However, only patients treated with a cocktail of drugs showed improvement at three months following treatment.

[Short-term and medium-term efficacy of mesotherapy in patients with lower back pain due to spondyloarthrosis]. / Efficacia della mesoterapia a breve e medio termine in pazienti affetti da lombalgia muscolotensiva da spondilartrosi.

Mesotherapy is an intradermal treatment for patients with local pain. The literature describes the efficacy of mesotherapy in the treatment of musculoskeletal disorders measuring a reduction of analgesic drug intake and of healthcare spending. The aim of this study was to measure the effects of mesotherapy on pain and disability in patients with low back pain due to spondyloarthrosis.

[Case report: Iatrogenic shoulder pain syndrome following spinal accessory nerve injury during lateral cervical neck dissection for tongue cancer: the role of rehabilitation and ethical-deontological issues]. / Caso clinico di sindrome della spalla dolorosa post lesione iatrogena del nervo accessorio spinale in seguito a svuotamento latero-cervicale del collo per carcinoma della lingua: ruolo della riabilitazione e aspetti etico-deontologici.

The shoulder pain syndrome is the most frequent complication of lateral cervical neck dissection and may be caused by iatrogenic injury to the spinal accessory nerve, causing pain and functional limitation of the upper limb and of the cervical spine. Interdisciplinary collaboration and early rehabilitation can reduce the consequences of disability and the possible issues that can arise due to inadequate management of the problem.

Are mast cells important in diabetes?

Diabetes is a metabolic disorder characterized by hyperglycemia and associated with microvascular and macrovascular syndromes mediated by mast cells. Mast cells are activated through cross-linking of their surface high affinity receptors for IgE (FcRI) or other antigens, leading to degranulation and release of stored inflammatory mediators, and cytokines/chemokines without degranulation. Mast cells are implicated in innate and acquired immunity, inflammation and metabolic disorders such as diabetes. Histamine and tryptase genes in mast cells are overexpressed in pancreatic tissue of type 2 diabetes mellitus (T2DM) patients. Histamine is a classic inflammatory mediator generated by activated receptors of mast cells from the histamine-forming enzyme histidine decarboxylase (HDC), which can be activated by two inflammatory chemokines, RANTES and MPC1, when injected intramuscularly or intradermally in mice. This activation is inhibited in genetically mast cell-deficient W/Wv mice, which show higher insulin sensitivity and glucose tolerance. This study contributes to understanding the mechanism by which mast cells profoundly affect diabetes, and their manipulation could represent a new therapeutic strategy. However, further studies are needed to clarify the role of mast cells in inflammation and metabolic disorders such as diabetes.