Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in ...inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33 and neurotensin. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved. Preliminary evidence suggests that mitochondrial function and dynamics control mast cell degranulation, but not selective release. Recent findings also indicate that mast cells have immunomodulatory properties. Understanding selective release of mediators could explain how mast cells participate in numerous diverse biologic processes, and how they exert both immunostimulatory and immunosuppressive actions. Unraveling selective mast cell secretion could also help develop unique mast cell inhibitors with novel therapeutic applications. This article is part of a Special Issue entitled: Mast cells in inflammation.
► Mast cells release pro-inflammatory mediators selectively without degranulation. ► Mast cells are activated by CRH released under stress. ► Neuropeptide mast cell triggers have synergistic action with cytokines, like IL-33. ► Unique flavonoid combinations can effectively block mast cell secretion. ► Mast cells may serve as new therapeutic targets for psoriasis and multiple sclerosis.
Summary
Allergic inflammation is a type 2 immune disorder classically characterized by high levels of immunoglobulin E (IgE) and the development of Th2 cells. Asthma is a pulmonary allergic ...inflammatory disease resulting in bronchial hyper‐reactivity. Atopic asthma is defined by IgE antibody‐mediated mast cell degranulation, while in non‐atopic asthma there is no allergen‐specific IgE and more involvement of innate immune cells, such as basophils, group 2 innate lymphoid cells (ILC2), and eosinophils. Recently, protease allergens were shown to cause asthmatic responses in the absence of Th2 cells, suggesting that an innate cell network (IL‐33/TSLP‐basophil‐ILC2‐IL‐5/IL‐13 axis) can facilitate the sensitization phase of type 2 inflammatory responses. Recent evidence also indicates that in the chronic phase, these innate immune cells directly or indirectly contribute to the adaptive Th2 cell responses. In this review, we discuss the role of Th2 cytokines (IL‐4 and IL‐13) and innate immune cells (mast cells, basophils, ILC2s, and dendritic cells) in the cross‐talk between innate and adaptive inflammatory responses.
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.
•A new model for the development of mast cell progenitors is proposed.•Methods used to quantify mast cell progenitors are described.•Regulators controlling the migration of mast cell progenitors into ...tissues are discussed.
Mast cells in tissues are developed from mast cell progenitors emerging from the bone marrow in a process highly regulated by transcription factors. Through the advancement of the multicolor flow cytometry technique, the mast cell progenitor population in the mouse has been characterized in terms of surface markers. However, only cell populations with enriched mast cell capability have been described in human. In naïve mice, the peripheral tissues have a constitutive pool of mast cell progenitors. Upon infections in the gut and in allergic inflammation in the lung, the local mast cell progenitor numbers increase tremendously. This review focuses on the origin and development of mast cell progenitors. Furthermore, the evidences for cells and molecules that govern the migration of these cells in mice in vivo are described.
Mast cells are so widely recognized as critical effector cells in allergic disorders and other immunoglobulin E-associated acquired immune responses that it can be difficult to think of them in any ...other context. However, mast cells also can be important as initiators and effectors of innate immunity. In addition, mast cells that are activated during innate immune responses to pathogens, or in other contexts, can secrete products and have cellular functions with the potential to facilitate the development, amplify the magnitude or regulate the kinetics of adaptive immune responses. Thus, mast cells may influence the development, intensity and duration of adaptive immune responses that contribute to host defense, allergy and autoimmunity, rather than simply functioning as effector cells in these settings.
Background In human subjects platelet-activating factor (PAF) concentrations are markedly increased in the plasma after anaphylactic reactions, and these correlate strongly with the severity of the ...response. The mechanism for the systemic spread of mast cell (MC) activation in anaphylaxis is often assumed to relate to the hematogenous spread of allergen, but this is implausible, and amplification mechanisms need to be considered. Objective We have investigated the ability of PAF to induce human MC degranulation using skin, lung, and peripheral blood (PB)–derived cultured MCs and the signaling pathways activated in PB-derived MCs in response to PAF. Methods The expression of PAF receptor was investigated by means of RT-PCR and Western blot analysis. Cell-signaling pathways in PB-derived MCs in response to PAF were investigated by analyzing the effect of various inhibitors and the silencing of phospholipase C (PLC) mRNA on PAF-mediated histamine release. Results We show for the first time that PAF induces histamine release from human lung MCs and PB-derived MCs but not skin MCs. Activation of PAF receptor–coupled Gαi leads to degranulation through PLCγ1 and PLCβ2 activation in human MCs. PAF-induced degranulation was rapid, being maximal at 5 seconds, and was partially dependent on extracellular Ca2+. Conclusion Our findings provide a mechanism whereby PAF mediates an amplification loop for MC activation in the generation of anaphylaxis.
Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset ...of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.
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•Irritant dermatitis requires MC degranulation, substance P, and MrgprB2•MrgprD-expressing neurons release glutamate that modulates dermal MC responsiveness•Small-molecule agonism of MrgprD-expressing neurons suppresses MC activation•Nonpeptidergic MrgprD-expressing neurons have immunomodulatory function
A subset of sensory neurons marked by MrgprD maintain skin homeostasis by suppressing mast cell inflammatory responses.
Summary
Glia and microglia in particular elaborate pro‐inflammatory molecules that play key roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative ...diseases. Microglia respond also to pro‐inflammatory signals released from other non‐neuronal cells, mainly those of immune origin such as mast cells. The latter are found in most tissues, are CNS resident, and traverse the blood–spinal cord and blood–brain barriers when barrier compromise results from CNS pathology. Growing evidence of mast cell–glia communication opens new perspectives for the development of therapies targeting neuroinflammation by differentially modulating activation of non‐neuronal cells that normally control neuronal sensitization – both peripherally and centrally. Mast cells and glia possess endogenous homeostatic mechanisms/molecules that can be up‐regulated as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N‐acylethanolamine family. One such member, N‐palmitoylethanolamine is proposed to have a key role in maintenance of cellular homeostasis in the face of external stressors provoking, for example, inflammation. N‐Palmitoylethanolamine has proven efficacious in mast‐cell‐mediated experimental models of acute and neurogenic inflammation. This review will provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells and the possibility that mast cell–microglia cross‐talk contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerates disease progression, as well as promoting pain transmission pathways. We will conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings.
Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing ...numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of 'MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D(2), or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets.
FcεRI-dependent activation and degranulation of mast cells (MC) play an important role in allergic diseases. We have previously demonstrated that triphenylphosphonium (TPP)-based antioxidant SkQ1 ...inhibits mast cell degranulation, but the exact mechanism of this inhibition is still unknown. This study focused on investigating the influence of TPP-based compounds SkQ1 and C12TPP on FcεRI-dependent mitochondrial dysfunction and signaling during MC degranulation.
MC were sensitized by anti-dinitrophenyl IgE and stimulated by BSA-conjugated dinitrophenyl. The degranulation of MC was estimated by β-hexosaminidase release. The effect of TPP-based compounds on FcεRI-dependent signaling was determined by Western blot analysis for adapter molecule LAT, kinases Syk, PI3K, Erk1/2, and p38. Fluorescent microscopy was used to evaluate mitochondrial parameters such as morphology, membrane potential, reactive oxygen species and ATP level.
Pretreatment with TPP-based compounds significantly decreased FcεRI-dependent degranulation of MC. TPP-based compounds also prevented mitochondrial dysfunction (drop in mitochondrial ATP level and mitochondrial fission), and decreased Erk1/2 kinase phosphorylation. Selective Erk1/2 inhibition by U0126 also reduced β-hexosaminidase release and prevented mitochondrial fragmentation during FcεRI-dependent degranulation of MC.
These findings expand the fundamental understanding of the role of mitochondria in the activation of MC. It also contributes to the rationale for the development of mitochondrial-targeted drugs for the treatment of allergic diseases.
Mast cell degranulation is accompanied by mitochondrial fragmentation mediated by Erk1/2 activity. Mitochondria-targeted TPP-based compounds SkQ1 and C12TPP accumulate in mitochondria and decrease mast cell degranulation by preventing Erk1/2-dependent mitochondrial dysfunction. Display omitted
•FcεRI-dependent degranulation of RBL-2H3 cells is accompanied by mitochondrial fragmentation and dysfunction.•The mitochondrial fission is mediated by Erk1/2 activity.•TPP-based compounds inhibit FcεRI-dependent degranulation of mast cells.•TPP-based compounds decrease Erk1/2 phosphorylation during mast cell FcεRI-dependent degranulation.•TPP-based compounds prevent mitochondrial dysfunction during mast cell FcεRI-dependent degranulation.
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