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.

Mast cells have existed long before the development of adaptive immunity, although they have been given different names. Thus, in the marine urochordate Styela plicata, they have been designated as test cells. However, based on their morphological characteristics (including prominent cytoplasmic granules) and mediator content (including heparin, histamine, and neutral proteases), test cells are thought to represent members of the lineage known in vertebrates as mast cells. So this lineage presumably had important functions that preceded the development of antibodies, including IgE. Yet mast cells are best known, in humans, as key sources of mediators responsible for acute allergic reactions, notably including anaphylaxis, a severe and potentially fatal IgE-dependent immediate hypersensitivity reaction to apparently harmless antigens, including many found in foods and medicines. In this review, we briefly describe the origins of tissue mast cells and outline evidence that these cells can have beneficial as well as detrimental functions, both innately and as participants in adaptive immune responses. We also discuss aspects of mast cell heterogeneity and comment on how the plasticity of this lineage may provide insight into its roles in health and disease. Finally, we consider some currently open questions that are yet unresolved.

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.

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Highlights d The mammalian receptor Mrgprb2 and MRGPRX2 can detect bacterial QSMs d QSM detection by Mrgprb2 and MRGPRX2 in mast cells elicits antibacterial mediator release d Mrgprb2 recognition of QSMs is critical for an effective immune response to bacteria d Pharmacologic activation of Mrgprb2 and MRGPRX2 enhances bacterial clearance

IntroductionMast cells are known to play a pivotal role in allergic hypersensitivity reaction and, more generally, in inflammation. 1,2 By virtue of their strategic and widespread location in tissues, namely at host-environment interface, and of their functional characteristics, mast cells behave as sentinels of the immune system. 3 Once activated, mast cells release several preformed and de novosynthesized mediators (including histamine, proteases, leukotrienes, prostaglandins, and various cytokines and chemokines), resulting in the recruitment and activation of other immune cells. 3 Several lines of evidence highlight an emerging role of mast cells in numerous steps of innate and adaptive immune responses, indicating that their contribution to immunity goes far beyond their well-known role in allergy. [3][4][5][6][7][8] Functional interplay between mast cells and T cells has been suggested by studies that document colocalization of activated mast cells and T cells in inflamed tissues 9,10 or involvement of mast cells in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. [11][12][13] Additional lines of evidence show that mast cells can contribute to the development of different T cell-associated responses by influencing the activation, the proliferation, the differentiation, and the recruitment of T cells. 7,14,15 Recent in vitro studies showed that IgE-activated mast cells can enhance T-cell proliferation by a mechanism involving tumor necrosis factor ␣ (TNF-␣) secretion, cell contact, and mast cell expression of OX40L. 6,7 In turn, it has been shown that activated T cells can induce in vitro histamine, TNF-␣, matrix metalloproteinase-9 secretion, and interleukin 4 (IL-4) mRNA expression in mast cell subsets. [16][17][18] Finally, mast cells have been reported to promote in vivo T-cell migration to inflammatory sites by secreting chemotactic factors, such as lymphotactin and IL-16 19 and to orient Th differentiation via the production of 21 Taken together these studies highlight the existence of functionally important mast cell/T-cell crosstalk and raise the question of whether mast cell/T-cell cognate interactions might occur in the course of immune responses.Immunological synapses (ISs) are the morphologic manifestation of the cognate interactions occurring between T cells and other cells of the immune system serving as antigen-presenting cells (APCs). These specialized areas of signal transduction, formed at the T cell/APC contact site, are characterized by large scale clustering and segregation of surface molecules and intracellular signaling components. [22][23][24] Among the different molecular rearrangements occurring at the IS, the polarization of T-cell Golgi apparatus toward the APCs for polarized secretion is a distinctive, rapid, and efficient T-cell response, occurring within minutes after T cell/APC encounter both in resting and activated CD4 ϩ and CD8 ϩ T cells. [25][26][27] It is, therefore, considered, together with T-cell receptor (TCR) enrichment into the IS, a morphol...

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.