PubMed RSS Feed - -Role of MrgprB2 in Rosacea-like Inflammation in Mice: Modulation by βarrestin2

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J Invest Dermatol. 2022 May 26:S0022-202X(22)00403-1. doi: 10.1016/j.jid.2022.05.005. Online ahead of print.

ABSTRACT

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 rosacea patients display higher frequencies of MCs expressing Mas-related G protein-coupled receptor (GPCR)-X2 (MRGPRX2; mouse counterpart MrgprB2) when compared to normal skin. Intradermal injection of LL-37 in wild-type (WT) mice resulted in MC recruitment, expression of inflammatory mediators and the development of rosacea-like inflammation. These responses were substantially reduced in MrgprB2^-/^- mice and abolished in MC deficient W^sh/W^sh mice. βarrestin2 is an adaptor protein that regulates GPCR 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 βarrestin2 when compared to control mice. Interestingly, absence of βarrestin2 resulted in enhanced cofilin phosphorylation and substantial inhibition of LL-37-induced chemotaxis of mouse peritoneal MCs (PMCs). Furthermore, LL-37-induced ERK1/2 phosphorylation, NF-κB activation and proinflammatory cytokine/chemokine production were reduced in βarrestin2^-/^- PMCs when compared to WT cells. These findings suggest that MRGPRX2/B2 participates in rosacea and βarrestin2 contributes to its pathogenesis by promoting cofilin dephosphorylation, ERK1/2 and NF-κB phosphorylation, MC chemotaxis and chemokine/cytokine generation.

PMID:35644498 | DOI:10.1016/j.jid.2022.05.005

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