The study shows that the peptide LL-37 can trigger skin inflammation similar to rosacea by activating mast cells through a receptor called MRGPRX2 (or MrgprB2 in mice). Mice that lack this receptor or lack mast cells have far less inflammation, and removing a helper protein called β‑arrestin‑2 also reduces the reaction.

Cathelicidin LL-37‒mediated activation of mast cells (MCs) has been implicated in the pathogenesis of rosacea, but the receptor involved and the mechanism of its activation and regulation remain unknown. We found that skin biopsies from patients with rosacea display higher frequencies of MCs expressing MRGPRX2 (mouse counterpart MrgprB2) than normal skin. Intradermal injection of LL-37 in wild-type mice resulted in MC recruitment, expression of inflammatory mediators, and development of rosacea-like inflammation. These responses were substantially reduced in MrgprB2^{‒/‒} mice and abolished in MC deficient W^sh/W^sh mice. β-arrestin 2 is an adaptor protein that regulates G protein-coupled receptor function by receptor desensitization and also by activation of downstream signaling. We found that LL-37‒induced rosacea-like inflammation was significantly reduced in mice with MC-specific deletion of β-arrestin 2 compared with that in control mice. Interestingly, the absence of β-arrestin 2 resulted in enhanced cofilin phosphorylation and substantial inhibition of LL-37‒induced chemotaxis of mouse peritoneal MCs. Furthermore, LL-37‒induced extracellular signal‒regulated kinase 1/2 phosphorylation, NF-κB activation, and proinflammatory cytokine/chemokine production were reduced in β-arrestin 2^{‒/‒} peritoneal MCs compared with those in wild-type cells. These findings suggest that MRGPRX2/B2 participates in rosacea and that β-arrestin 2 contributes to its pathogenesis by promoting cofilin dephosphorylation, extracellular signal‒regulated kinase 1/2 and NF-κB phosphorylation, MC chemotaxis, and chemokine/cytokine generation.