The pseudo-allergic/neurogenic route of mast cell activation via MRGPRX2: discovery, functional programs, regulation, relevance to disease, and relation with allergic stimulation
Magda Babina
Abstract
Mast cells (MCs) form operating units with sensory nerves and can contribute to sensations of itch and pain. However, it remained enigmatic for decades how MCs are actually activated in the absence of atopy. MRGPRX2 was discovered only recently but has already changed our view of MC biology. As the receptor of multiple endogenous and exogenous ligands, including substance P and various drugs, MRGPRX2 can be viewed as the missing link underlying clinically relevant MC degranulation in the context of drug-triggered pseudo-allergy and autonomous (eg, neuronal) MC activation in disease. Its existence explains previous findings that remained inexplicable for a long time. The confinement of MRGPRX2 to MCs, and even only to the subgroup of MC TC -type MCs, makes research in this field exciting from a theoretical as well as from a translational or pharmacological perspective alike. In this review, I will first give a brief overview of MCs, their subsets and modes of activation, then briefly touch on the history of MRGPRX2 discovery, summarize some recent advances regarding ligands, functional aspects and regulation by extracellular cues, and recapitulate the emerging role of the MRGPRX2 system in health and disease. Finally, a concise comparison between MRGPRX2 and FcεRI will be presented, contrasting key characteristics of the 2 dominant ways of MC activation. There is a huge disproportion in our understanding of FcεRI-triggered versus MRGPRX2-triggered events, but since research into the latter is in full swing, some of the missing pieces of the puzzle are likely to be filled in soon.