Multifaceted MRGPRX2: New insight into the role of mast cells in health and disease

Cutaneous mast cells (MCs) express Mas-related G protein- coupled receptor-X2 (MRGPRX2; mouse ortholog MrgprB2), which is activated by an ever-increasing number of cationic ligands. Antimicrobial host defense peptides (HDPs) generated by keratinocytes contribute to host defense likely by 2 mechanisms, one involving direct killing of microbes and the other via MC activation through MRGPRX2. However, its inappropriate activation may cause pseudoallergy and likely contribute to the pathogenesis of rosacea, atopic dermatitis, allergic contact dermatitis, urticaria, and mastocytosis. Gain and loss-of-function missense single nucleotide polymorphisms in MRGPRX2 have been identified. The ability of certain ligands to serve as balanced or G protein-biased agonists has been defined. Small-molecule HDP mimetics that display both direct antimicrobial activity and activate MCs via MRGPRX2 have been developed. In addition, antibodies and reagents that modulate MRGPRX2 expression and signaling have been generated. In this article, we provide a comprehensive update on MrgprB2 and MRGPRX2 biology. We propose that harnessing MRGPRX2's host defense function by small molecule HDP mimetics may provide a novel approach for the treatment of antibiotic-resistant cutaneous infections. In contrast, MRGPRX2-specific antibodies and inhibitors could be used for the modulation of allergic and inflammatory diseases that are mediated via this receptor. (J Allergy Clin Immunol 2021;148:293-308.)