Gianpaolo Ronconi

Mast cells emerge as mediators of atherosclerosis: Special emphasis on IL-37 inhibition

In atherosclerosis lipoproteins stimulate the innate immune response, leading to the release of inflammatory cytokines and chemokines. Hypercholesterolemia may activate the synthesis and release of inflammatory cytokines such as IL-1, which induces TNF release in mast cells (MCs). IL-1 and IL-1 family members orchestrate a broadening list of inflammatory diseases, including atherosclerosis. MCs are implicated in the pathophysiology of several diseases including allergy and inflammation. Activated MCs, located perivascularly, contribute to inflammation in atherosclerosis by producing inflammatory cytokines. MC IL-1-activation leads to the immediate release of inflammatory chemical mediators and TNF, and late inflammatory compounds such as cytokines. MCs can be activated by exogenous cytokines, antigens, microbial products (LPS) and neurotransmitters and generate IL-1 beta, TNF and several other inflammatory cytokines/chemokines along with PGD2, leukotrienes, histamine and proteases. MCs activated with IL-1 induce selective release of IL-6 without degranulation. TNF emerges as one of the most potent inflammatory cytokines involved in the response due to LDL. Cytokines, such as IL-1, IL-6, IL-33 and TNF, are generated in the inflammatory sites by both macrophages and MCs, mediating atherosclerosis. IL-37 (IL-1 family member 7) binds IL-18Ra chain and acts by an intracellular mechanism down-regulating the expression of pro-inflammatory signals cJun, MAP kinase p38a, STAT transcription factors and p53. Blocking IL-1 with IL-37 alleviates the symptoms in patients with inflammatory diseases including arteriosclerosis. The impact of IL-37 on inflammatory cytokines mediating atherosclerosis is beneficial and protective. However, more studies are needed to better define this mechanism and the safety and tolerability of IL-37.

Link between mast cells and bacteria: Antimicrobial defense, function and regulation by cytokines.

Bacteria and their products, such as LPS, act on mast cells (MCs) to induce the secretion of multiple cytokines, including IL-1, TNF, IL-18 and IL-33, which can be dosed in the site of infected tissues. Antigen-binding IgE cross-links FcεRI on mast cells involves the generation and activation of PKCδ, ERK, tyrosine kinases (Syk and Lyn) and mitogen-activated protein kinases (MAPKs), inducing the release of chemical mediators which provoke inflammation and hypersensitive reaction. Other stimuli, including, cytokines, neuropeptides, chemical and physical activators, can also act on MCs to release a plethora of inflammatory compounds. Activated MCs produce a broad spectrum of inflammatory cytokines, chemokines, lipid compounds and vasoactive amines, all involved in immune response. By producing TNF, MCs have an antibacterial defense and a protective function; while pathogenic bacteria and their products, such as LPS, have an inflammatory response through MC activation. LPS binding TLR4 produce MC generation IL-1 family members, and chemokines, which may recruit inflammatory cells at the infection site; whereas in KitW/W-v mice, where MCs are genetically absent, the inflammatory effect is not present. We report for the first time a link between MCs and bacteria emphasizing the mediation of inflammatory cytokines/chemokines. We can conclude that mast cells fight bacteria, and their immune response is perfectly integrated in the immune network. We hope that the understanding of microbial and mast cell interaction leads to more efficient therapeutic development in relation to microbial resistance.

Impact of mast cells in mucosal immunity of intestinal inflammation: Inhibitory effect of IL-37

Abstract Mast cells (MCs) are implicated in an array of diseases, especially those involving a mucosal surface, including intestine. On appropriate activation from cytoplasmatic granules, MCs release preformed chemical mediators and generate inflammatory lipids and cytokines/chemokines. Intracellular signal and Lyn activation pathways can cause the degranulation of MCs and the generation of lipid mediators and cytokines/chemokines. MCs undergo maturation and polarization in gut mucosal surfaces where they are constitutively present, and can alter intestinal permeability, an important factor in many inflammatory mucosal disorders including autoimmune diseases. On the other hand, since they are immununosuppressive, MCs have potential anti‐inflammatory properties by producing TGF‐&bgr;1, interleukin (IL)‐4, IL‐10, IL‐13 and histamine. In addition, MC chymase, located in the sub‐mucosa, acts on intestinal permeability by protecting the bowel. To carry the inflammatory response, MCs need to be attracted by CC chemokines such as RANTES (CCL5) and MCP‐1(CCL2), an effect absent in genetically W/Wv mast cell‐deficient mice, where the inflammatory reaction is not present. Here, we focused our attention on recent findings regarding how MCs can initiate and develop the cellular immune response in the gut and mediate inflammation, an effect that can be inhibited by IL‐37. These studies contribute to clarify the mechanisms by which MCs profoundly affect immunity and inflammation of the intestine.

Potential therapeutic use of IL-37: a key suppressor of innate immunity and allergic immune responses mediated by mast cells

The host response to either exogenous or endogenous insults produces a series of changes, characterized by alterations in immunological functions and generation of mediators called cytokines which include the interleukin-1 (IL-1) family members. IL-1 acts as a hormone mediating the host responses to infection and inflammation. Blocking inflammatory IL-1 family members can be effective against inflammatory disorders, including allergies. IL-37, (formerly IL-1 family member 7), emerges as an inhibitor of innate and adaptive immunity by reducing circulating and organ cytokine levels. IL-37, mainly expressed in dendritic cells, monocytes, and plasma cells after TIR ligand activation, inhibits inflammatory cytokines and augments the level of anti-inflammatory IL-10. IL-37 is involved in allergic reaction and its expression in dendritic cells causes tollerogenicity and inhibits inflammatory response. Mast cells (MCs) are ubiquitous in the body, reside in numerous mucosal tissues, and are mediators of allergic reaction, and innate and adaptive immunity. MCs are important regulators of cytokine generation in the course of inflammatory responses and allergy, and are implicated in the pathophysiology of allergic asthma. Cysteine protease caspase-1 activation leads to the cleavage of pro-form of IL-1 into active mature IL-1 which is present in stimulated and unstimulated inflammatory MCs. Inflammatory cytokine inhibition, along with the augmentation of anti-inflammatory IL-10 by IL-37, is certainly beneficial and improves the pathogenesis of allergic disorders. However, in these studies, the exact mechanism(s) of IL-37-induced anti-inflammatory and anti-allergic activity along with its side effect(s) remain to be determined.

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 (Fcuf065RI) 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.

Critical role of inflammatory mast cell in fibrosis: Potential therapeutic effect of IL-37

Fibrosis involves the activation of inflammatory cells, leading to a decrease in physiological function of the affected organ or tissue.

Activated Mast Cells Mediate Low-Grade Inflammation in Type 2 Diabetes: Interleukin-37 Could Be Beneficial

Mast cells (MCs) promote guest immune responses to parasites and play a critical role in allergic and inflammatory reactions. Once they have been activated, MCs release highly inflammatory compounds that can provoke serious pathologic signs that can lead to death. MCs generate a number of preformed, de novo synthesized compounds and inflammatory cytokine/chemokine synthesis in response to the high-affinity (Kd=10-10 M) immunoglobulin E receptor triggering. Circulating MC progenitors migrate into arterial intima and develop lesions, mediating inflammation. They are involved in several disorders, including metabolic diseases, such as type 2 diabetes mellitus, in which endothelial cells release several inflammatory compounds during acute and chronic vascular damage. Certain inflammatory cytokines, such as interleukin (IL)-1 and IL-33, not only are produced by MCs but also may activate them. These effects mediate systemic inflammatory responses in metabolic disorders. Proinflammatory cytokines, such as tumor necrosis factor, IL-33 and IL-6, secreted by MCs and other immune cells, contribute to insulin resistance by activating kinases. IL-37 (IL-1 family member 7), one of the latest cytokines discovered, binds the IL-18 receptor alpha (IL-18Rα) chain and suppresses innate and acquired immunity, with a therapeutic effect. It also inhibits cytokine levels, including IL-6, IL-18, IL-33, tumor necrosis factor and IL-1, and may improve insulin production and, therefore, the pathogenesis of diabetes, stroke and cardiovascular health. This describes a new concept of inhibition of and cure for inflammatory diseases. However, the safety, dosage and tolerability of this novel therapeutic agent, IL-37, still remains to be determined.

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

AbstractObjectiveThe 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.MethodsWe evaluated allograft rejection on the experience of our experimental data and using the relevant literature.nResultsMCs 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. nConclusionIL-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 mast cells in depression disorder: inhibitory effect of IL-37 (new frontiers)

The purpose of this article is to study the involvement of inflammatory mast cells (MCs) in depression which may be inhibited by IL-37. We evaluate mast cells in depression on the basis of our previous experimental data, and using the most relevant studies reported in the literature. Dysfunction of mood, feelings, and thoughts is a major risk factor for several metabolic diseases and may influence the physiology of the body leading to depression. Depression, present in mastocytosis, is an important endogenous process that promotes the activation of meningeal cell receptors through a low-grade neurogenic chronic inflammation, and MCs. Mast cells are localized along meningeal blood vessels and connective tissues, as well as between the ganglion cells and nerve fibers. They are present in the hypothalamus of mammalian brains capable of communication with nerves. MCs are classically activated by binding to IgE cross-link FcεRI high-affinity receptor leading to release a plethora of mediators responsible for the generation of inflammatory cytokines. Corticotropin-releasing hormone (CRH), produced by MCs, has been found in microglial cells where it regulates immune cells and contributes to the pathogenesis of neurodegenerative diseases including depression. Inflammatory cytokines released by MCs aggravate depression and could be partially inhibited by IL-37. A detailed understanding of the interaction between the immune system, including MCs and depression, is necessary in order to address an effective therapy which could include IL-37. As a consequence, the concepts reviewed here have treatment implications.

Impact of Fungi on Immune Responses

Spores and fungal fragments found in indoor and outdoor environments originate from opportunistic fungi and they can contribute to inflammatory responses, causing a broad range of symptoms. Papers were selected and reviewed with an emphasis on the molecular mechanisms involved in the effect of fungi on immune cells, especially mast cells (MCs). Fungi can bind to antibodies and complement them, allowing them to be recognized by cells of the innate immune system, including macrophages, dendritic cells, and MCs, which are then stimulated via Toll-like receptor signaling. Fungi can cause diseases mediated by MCs and aggravate allergic inflammation. Immunosuppressed subjects can be particularly susceptible to developing diseases caused by opportunistic fungi. Mold also liberates mycotoxins that could be on volatile spores and stimulate MCs to secrete pro-inflammatory cytokines/chemokines, but this mechanism is not known. Fungi can activate the immune system directly or through mycotoxins, leading to stimulation of immune cells and chronic neuroinflammatory symptoms. Some of these processes may be inhibited by the new anti-inflammatory cytokine interleukin 37.