Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.

# The following authors contributed equally Life Sciences Reporting Summary. Further information on experimental design and reagents is available in the Life Sciences Reporting Summary. Data availability. The data that support the findings of this study are available from the corresponding author Nicolas Gaudenzio upon request.

Reber et al. reveal a protective function for neutrophils after lethal endotoxin challenge using a novel mouse model of diphtheria toxin–inducible neutropenia. Neutrophil expression of myeloperoxidase (MPO) is necessary for this protection. These findings imply that neutrophils protect the host by limiting the extent of LPS-induced pathology in an MPO-dependent manner.

Mast cells (MCs) are cells of hematopoietic origin that normally reside in mucosal tissues, often near epithelial cells, glands, smooth muscle cells, and nerves. Best known for their contributions to pathology during IgE-associated disorders such as food allergy, asthma, and anaphylaxis, MCs are also thought to mediate IgE-associated effector functions during certain parasite infections. However, various MC populations also can be activated to express functional programs – such as secreting pre-formed and/or newly synthesized biologically active products – in response to encounters with products derived from diverse pathogens, other host cells (including leukocytes and structural cells), damaged tissue, or the activation of the complement or coagulation systems, as well as by signals derived from the external environment (including animal toxins, plant products, and physical agents). In this review, we will discuss evidence suggesting that MCs can perform diverse effector and immunoregulatory roles that contribute to homeostasis or pathology in mucosal tissues.

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Mast cells regulate the immunological responses causing allergy and autoimmunity, and contribute to the tumor microenvironment through generation and secretion of a broad array of preformed, granule-stored and de novo synthesized bioactive compounds. The release and production of mast cell mediators is the result of a coordinated signaling machinery, followed by the FcεRI and FcγR antigen ligation. In this review, we present the latest understanding of FcεRI and FcγR signaling, required for the canonical mast cell activation during allergic responses and anaphylaxis. We then describe the cooperation between the signaling of FcR and other recently characterized membrane-bound receptors (i.e., IL-33R and thymic stromal lymphopoietin receptor) and their role in the chronic settings, where mast cell activation is crucial for the development and the sustainment of chronic diseases, such as asthma or airway inflammation. Finally, we report how the FcR activation could be used as a therapeutic approach to treat allergic and atopic diseases by mast cell inactivation. Understanding the magnitude and the complexity of mast cell signaling is necessary to identify the mechanisms underlying the potential effector and regulatory roles of mast cells in the biology and pathology of those disease settings in which mast cells are activated.Keywords: FcεRI r FcγR r IL-33 r mast cells r TSLP IntroductionMast cells originate in the BM from a lineage-specific multipotent hematopoietic progenitor, circulate as CD34 + precursors until they migrate to tissues and mature into effector cells in the proximity of organs and blood vessels. Mast cells respond to antigenic stimulation through the cross-linking of immunoglobulin E (IgE) bound to high-affinity receptors for IgE (FcεRI) and the activation of the FcγR after IgG binding (reviewed in [1,2]). Upon activation, mast cells release either preformed, granule-stored mediators, such as histamine and proteases, or newly generated mediators, such as eicosanoids, cytokines, and chemokines [3]. Although the basic molecular mechanisms of Ig:Fc activation have been extensively studied in the past 15 years [4][5][6], new molecules regulating the Correspondence: Dr. Barbara Frossi e-mail: barbara.frossi@uniud.it FcR-signaling cascades have recently been characterized, suggesting not only a still vivid interest in the field of mast cell activation and signaling, but also in identifying putative new therapeutic targets for intervention in mast cell dependent disorders. This review will focus on three aspects of mast cell activation/function. First, we give an essential but complete overview of the FcR-mediated activation in mast cells and report on recent advances in IgE-and IgG-mediated signaling. For clarity, we will dissect and analyze the signals derived from each pathway, with particular attention to the newly identified positive or negative molecular players describing -when possible -their implication toward degranulation and cytokine production. Second, we highlight the growing interest aroun...

Mast cells (MCs) are currently recognized as effector cells in many settings of the immune response, including host defense, immune regulation, allergy, chronic inflammation, and autoimmune diseases. MC pleiotropic functions reflect their ability to secrete a wide spectrum of preformed or newly synthesized biologically active products with pro-inflammatory, anti-inflammatory and/or immunosuppressive properties, in response to multiple signals. Moreover, the modulation of MC effector phenotypes relies on the interaction of a wide variety of membrane molecules involved in cell–cell or cell-extracellular-matrix interaction. The delivery of co-stimulatory signals allows MC to specifically communicate with immune cells belonging to both innate and acquired immunity, as well as with non-immune tissue-specific cell types. This article reviews and discusses the evidence that MC membrane-expressed molecules play a central role in regulating MC priming and activation and in the modulation of innate and adaptive immune response not only against host injury, but also in peripheral tolerance and tumor-surveillance or -escape. The complex expression of MC surface molecules may be regarded as a measure of connectivity, with altered patterns of cell–cell interaction representing functionally distinct MC states. We will focalize our attention on roles and functions of recently discovered molecules involved in the cross-talk of MCs with other immune partners.

Background Animal models have demonstrated that allergen-specific IgG confers sensitivity to systemic anaphylaxis that relies on IgG receptors (FcγRs). Mouse IgG2a and IgG2b bind activating FcγRI, FcγRIII and FcγRIV, and inhibitory FcγRIIB; mouse IgG1 binds only FcγRIII and FcγRIIB. Although these interactions are of strikingly different affinities, these three IgG subclasses have been shown to enable induction of systemic anaphylaxis. Objective Determine which pathways control the induction of IgG1-, IgG2a- and IgG2b-passive systemic anaphylaxis. Methods Mice were sensitized with IgG1, IgG2a or IgG2b anti-TNP mAbs and challenged with TNP-BSA intravenously to induce systemic anaphylaxis that was monitored using rectal temperature. Anaphylaxis was evaluated in mice deficient for FcγRs, injected with mediator antagonists or in which basophils, monocyte/macrophages or neutrophils had been depleted. The expression of FcγRs was evaluated on these cells before and after anaphylaxis. Results Activating FcγRIII is the receptor primarily responsible for all three models of anaphylaxis, and subsequent down regulation of this receptor was observed. These models differentially relied on histamine release and on the contribution of mast cells, basophils, macrophages and neutrophils. Strikingly, basophil contribution and histamine predominance in IgG1- and IgG2b-mediated anaphylaxis correlated with the ability of inhibitory FcγRIIB to negatively regulate these models of anaphylaxis. Conclusion We propose that the differential expression of inhibitory FcγRIIB on myeloid cells and its differential binding of IgG subclasses controls the contributions of mast cells, basophils, neutrophils and macrophages to IgG subclass-dependent anaphylaxis. Collectively, our results unravel novel complexities in the involvement and regulation of cell populations in IgG-mediated reactions in vivo.