The MRGPRX2-substance P pathway regulates mast cell migration

Mast cells (MCs) are tissue-resident immune cells known to degranulate in response to FcεRI crosslinking or MRGPRX2 engagement. MCs are found close to nerves, but the mechanisms that regulate this privileged localization remain unclear. Here, we investigated MRGPRX2 expression patterns and specific activities in MCs. We show that MRGPRX2 expression is heterogeneous in human MC (hMC) progenitors and mature MCs. Substance P (SP) is a rapid and specific activator of MRGPRX2, and long-term supplementation of MCs with SP expands MRGPRX2-expressing cells. While high concentrations of SP induce rapid MC degranulation, low concentrations prompt immature MC chemotaxis. Lastly, we demonstrate that in inflammatory skin conditions like psoriasis, the number of MRGPRX2⁺ MCs is increased, and during <i>in vitro</i> skin reinnervation, MRGPRX2⁺ MCs preferentially reside in proximity to and migrate toward SP⁺ nerve fibers (NFs). This indicates that SP-MRGPRX2 signaling defines MC positioning and relocation within tissues and promotes immune cell-NF communication.