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Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1 , the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1 + Tac1 + nociceptor–MRGPRB2 + mast cell sensory clusters represents a key early event in the development of allergic skin reactions. Gaudenzio and colleagues show that house dust mite extracts directly activate TRPV1 + sensory neurons, which promote allergic skin inflammation by inducing the degranulation of mast cells through the release of the neuropeptide substance P and activation of MRGPRB2.

Mast cells are tissue-resident immune cells that play a key role in inflammation and allergy. Here we show that interaction of mast cells with antibody-targeted cells induces the polarized exocytosis of their granules resulting in a sustained exposure of effector enzymes, such as tryptase and chymase, at the cell–cell contact site. This previously unidentified mast cell effector mechanism, which we name the antibody-dependent degranulatory synapse (ADDS), is triggered by both IgE- and IgG-targeted cells. ADDSs take place within an area of cortical actin cytoskeleton clearance in the absence of microtubule organizing centre and Golgi apparatus repositioning towards the stimulating cell. Remarkably, IgG-mediated degranulatory synapses also occur upon contact with opsonized Toxoplasma gondii tachyzoites resulting in tryptase-dependent parasite death. Our results broaden current views of mast cell degranulation by revealing that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens for dedicated secretion and defence. Mast cells are tissue-resident immune cells important for clearance of parasitic worms but also mediating allergic reactions. Here Joulia et al . show that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens to increase efficiency and minimize off-target effects.

Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

ABSTRACT Mast cells (MC) are long‐lived important immune effectors that control inflammation, allergies, and innate immunity reactions, but the expression of specific markers in replicative and stress‐induced senescence in this cell type, together with its relevance in vivo, has not been described. Here, bone marrow‐derived MCs (BMMC) were generated from young C57BL6/J mice and kept in culture for a long time or treated with the well‐known stressor bacterial lipopolysaccharide (LPS) to promote replicative and stress‐induced senescence, respectively. Changes in size, granularity, and expression of p16INK4A and p21CIP1/WAF1, together with cell cycle arrest and senescence‐associated‐β‐Galactosidase (SA‐β‐Gal) activity, were observed after 12 weeks in culture, with minimal changes in cell viability but important modifications in cell metabolism. Senescence‐associated secretory phenotype (SASP) included IL‐23, IL‐6, and VEGF, among other cytokines and chemokines. Maximal FcεRI and TLR4‐dependent cell activation was diminished by replicative senescence in BMMC. Stress‐induced senescence produced cell cycle arrest, increased β‐Gal expression, and transient high cytokine expression. Utilizing aged MC‐deficient (c‐KitWsh/Wsh) and c‐KitWsh/Wsh mice reconstituted with MC, the exacerbated cytokine production observed in senescent cells was confirmed in the rapid, canonical MC‐dependent response to acute intraperitoneal LPS administration. Finally, high basal cytokine production was detected in MC purified from chronically LPS‐treated animals. Our data show that (1) senescence markers appear in replication and stress‐induced senescence of MCs; (2) basal and activated effector functions of MC are altered by senescence; and (3) aging is associated with increased MC‐dependent inflammatory responses. Our results show that senescence importantly affects MC function, which could contribute to inflammaging. Senescent mast cells express canonical senescence markers and develop a pro‐inflammatory phenotype characterized by SASP, increased MAPK and NFκB activation, and altered FcεRI and TLR4‐induced responses. Senescence causes increased mast cell‐dependent inflammaging and innate immunity responses in vivo.

Hematopoietic cells, including lymphoid and myeloid cells, can develop into phenotypically distinct 'subpopulations' with different functions. However, evidence indicates that some of these subpopulations can manifest substantial plasticity (that is, undergo changes in their phenotype and function). Here we focus on the occurrence of phenotypically distinct subpopulations in three lineages of myeloid cells with important roles in innate and acquired immunity: macrophages, mast cells and neutrophils. Cytokine signals, epigenetic modifications and other microenvironmental factors can substantially and, in some cases, rapidly and reversibly alter the phenotype of these cells and influence their function. This suggests that regulation of the phenotype and function of differentiated hematopoietic cells by microenvironmental factors, including those generated during immune responses, represents a common mechanism for modulating innate or adaptive immunity.

Autophagy is an evolutionally conserved, highly regulated catabolic process that combines cellular functions required for the regulation of metabolic balance under conditions of stress with those needed for the degradation of damaged cell organelles via the lysosomal machinery. The importance of autophagy for cell homeostasis and survival has long been appreciated. Recent data suggest that autophagy is also involved in non-metabolic functions that impact the immune system. Here, we reflect in two review articles the recent literature pointing to an important role for autophagy in innate immune cells. In this article, we focus on neutrophils, eosinophils, mast cells, and natural killer cells. We mainly discuss the influence of autophagy on functional cellular responses and its importance for overall host defense. In the companion review, we present the role of autophagy in the functions performed by monocytes/macrophages and dendritic cells.Involvement of autophagy in cellular functions of neutrophils, eosinophils, basophils, NK cells, and mast cells.

Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis. However, the mechanisms of JEV penetration of the blood-brain-barrier (BBB) remain poorly understood. Mast cells (MCs) are granulated innate immune sentinels located perivascularly, including at the BBB. Here we show that JEV activates MCs, leading to the release of granule-associated proteases in vivo. MC-deficient mice display reduced BBB permeability during JEV infection compared to congenic wild-type (WT) mice, indicating that enhanced vascular leakage in the brain during JEV infection is MC-dependent. Moreover, MCs promoted increased JEV infection in the central nervous system (CNS), enhanced neurological deficits, and reduced survival in vivo. Mechanistically, chymase, a MC-specific protease, enhances JEV-induced breakdown of the BBB and cleavage of tight-junction proteins. Chymase inhibition reversed BBB leakage, reduced brain infection and neurological deficits during JEV infection, and prolonged survival, suggesting chymase is a novel therapeutic target to prevent JEV encephalitis. How Japanese encephalitis virus (JEV) penetrates the blood-brain barrier (BBB) remains unclear. Here, using a genetic mouse model and a virulent JEV strain, the authors show that perivascular mast cells (MC) mediate JEV neuroinvasion and identify the MC-protease chymase as a potential therapeutic target.

Mast cells are a major component of the immune microenvironment in tumour tissues and modulate tumour progression by releasing pro‐tumorigenic and antitumorigenic molecules. Regarding the impact of mast cells on the outcomes of patients with lung adenocarcinoma (LUAD) patient, several published studies have shown contradictory results. Here, we aimed at elucidating the role of mast cells in early‐stage LUAD. We found that high mast cell abundance was correlated with prolonged survival in early‐stage LUAD patients. The mast cell‐related gene signature and gene mutation data sets were used to stratify early‐stage LUAD patients into two molecular subtypes (subtype 1 and subtype 2). The neural network‐based framework constructed with the mast cell‐related signature showed high accuracy in predicting response to immunotherapy. Importantly, the prognostic mast cell‐related signature predicted the survival probability and the potential relationship between TP53 mutation, c‐MYC activation and mast cell activities. The meta‐analysis confirmed the prognostic value of the mast cell‐related gene signature. In summary, this study might improve our understanding of the role of mast cells in early‐stage LUAD and aid in the development of immunotherapy and personalized treatments for early‐stage LUAD patients. Mast cell abundance and a mast cell‐related signature were correlated with survival in early‐stage lung adenocarcinoma patients. The mast cell‐related signature‐based neural network showed high accuracy in predicting response to immunotherapy.

The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct “subpopulations” of mast cells based on a relatively small number of biochemical characteristics. More recently, “subtypes” of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease.