Allergic FcεRI- and pseudo-allergic MRGPRX2-triggered mast cell activation routes are independent and inversely regulated by SCF

Abstract

While allergic mast cell (MC) degranulation occurs by FcεRI-aggregation and varies in strength among subjects, the analogous pseudo-allergic route was recently uncovered to proceed via MRGPRX2. Here, we examine inter-individual variability in skin MC responses to FcεRI-triggering versus those evoked by MRGPRX2. While population-based variability is comparable between the routes, FcεRI- and MRGPRX2-stimulated pathways are completely independent from each other, and responsiveness to one has therefore no predictive value for the other. Conversely, degranulation triggered by compound 48/80 is highly correlated to the process elicited by Substance P. MRGPRX2 mRNA shows pronounced population-based variability (coefficient of variation 102.9%). Surprisingly, SCF as the MC-supportive mediator par excellence potently inhibits pseudo-allergic degranulation, while it simultaneously promotes allergic stimulation via FcεRI. We conclude that SCF can have selective MC-dampening functions. Clinically, the data imply that subjects highly reactive in one pathway are not automatically hyper-responsive in terms of the alternative route.

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