Mast cells are powerful immune modulators of the tissue microenvironment. Within seconds of activation, these cells release a variety of preformed biologically active products, followed by a wave of mediator synthesis and secretion. Increasing evidence suggests that an intricate network of inhibitory and activating receptors, specific signaling pathways, and adaptor proteins governs mast cell responsiveness to stimuli. Here, we discuss the biological and clinical relevance of negative and positive signaling modalities that control mast cell activation, with an emphasis on novel FcεRI regulators, immunoglobulin E (IgE)-independent pathways [e.g., Mas-related G protein-coupled receptor X2 (MRGPRX2)], tetraspanins, and the CD300 family of inhibitory and activating receptors.

Department of Signal Transduction Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague Czech Republic

Division of Musculoskeletal and Dermatological Sciences Faculty of Biology Medicine and Health University of Manchester Manchester UK

Immunology and Allergy unit Department of Medicine Karolinska Institutet and Karolinska University Hospital Stockholm Sweden; Department of Medical Sciences Uppsala University Uppsala Sweden

INSERM U1149 Centre de Recherche sur l'Inflammation Paris France; CNRS ERL8252 Paris France; Université Paris Diderot Sorbonne Paris Cité Faculté de Médecine Site Xavier Bichat Inflamex Laboratory of Excellence Paris France

Pharmacology and Experimental Therapeutics Unit School of Pharmacy Institute for Drug Research Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel

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