LL-37-MRGPRX2-Mast Cell Signaling in Rosacea: Current Evidence and Directions for Human Studies

This critical narrative review examines evidence relevant to LL-37-Mas-related G protein-coupled receptor X2 (MRGPRX2)-mast-cell signaling in rosacea and considers the relevance of these findings to future human studies. Literature was identified through PubMed and Web of Science Core Collection searches, supplemented by examination of reference lists from relevant original studies and recent reviews. Human rosacea tissue studies show changes in mast-cell abundance or degranulation-associated staining and localize MRGPRX2 to lesional mast cells. Human mast-cell and receptor studies demonstrate LL-37-responsive MRGPRX2 calcium signaling and degranulation and show pharmacological inhibition of MRGPRX2-mediated responses. LL-37-induced mouse models support contributions of mast cells and murine Mas-related G protein-coupled receptor member B2 (MrgprB2), although human MRGPRX2 and murine MrgprB2 are pharmacologically distinct. Other LL-37-responsive pathways and downstream regulatory processes may also produce or modify similar mast-cell outcomes. Direct selective functional testing of MRGPRX2 in patients with rosacea remains lacking, and receptor-level functional findings and patient-level observations still arise largely from different study settings. Future human studies could therefore connect lesional MRGPRX2 status and selective receptor perturbation with proximal mast-cell responses and corresponding tissue or clinical changes within the same rosacea study setting. Under adequately designed study conditions, concordant findings may strengthen support for MRGPRX2 involvement, whereas partial, discordant, subgroup-restricted, or absent proximal responses may help refine its functional scope in human rosacea.