Emerging mechanisms contributing to mast cell-mediated pathophysiology with therapeutic implications

Mast cells are tissue-resident immune cells that play key roles in the initiation and perpetuation of allergic inflammation, usually through IgE-mediated mechanisms. Mast cells are, however, evolutionary ancient immune cells that can be traced back to urochordates and before the emergence of IgE antibodies, suggesting their involvement in antibody-independent biological functions, many of which are still being characterized. Herein, we summarize recent advances in understanding the roles of mast cells in health and disease, partly through the study of emerging non-IgE receptors such as the Mas-related G protein-coupled receptor X2, implicated in pseudo-allergic reactions as well as in innate defense and neuronal sensing; the mechano-sensing adhesion G protein–coupled receptor E2, variants of which are associated with familial vibratory urticaria; and purinergic receptors, which orchestrate tissue damage responses similarly to the IL-33 receptor. Recent evidence also points toward novel mechanisms that contribute to mast cell-mediated pathophysiology. Thus, in addition to releasing preformed mediators contained in granules and synthesizing mediators de novo, mast cells also secrete extracellular vesicles, which convey biological functions. Understanding their release, composition and uptake within a variety of clinical conditions will contribute to the understanding of disease specific pathology and likely lead the way to novel therapeutic approaches. We also discuss recent advances in the development of therapies targeting mast cell activity, including the ligation of inhibitory ITIM-containing receptors, and other strategies that suppress mast cells or responses to mediators for the management of mast cell-related diseases.