The neuroendocrine peptide catestatin promotes clearance of cutaneous Staphylococcus aureus through mast cell Mrgpr...

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of cutaneous infections, underscoring the need for alternative therapeutic strategies. Catestatin (CST), a neuroendocrine antimicrobial peptide produced by neurons and epithelial cells, has been implicated in skin defense against pathogens such as MRSA, though its mechanisms remain unclear. Here, we show that CST expression is upregulated in MRSA-infected skin wounds and that topical CST application significantly accelerates wound healing and reduces MRSA burden in infected murine cutaneous wounds. This effect is dependent on the mast cell-specific G protein-coupled receptor Mrgprb2, the murine ortholog of human MRGPRX2. Notably, CST treatment leads to Mrgprb2-dependent suppression of inflammatory cytokine production and leukocyte infiltration, alongside upregulation of the antimicrobial peptide β-defensin-14. In an immortalized human mast cell line, CST induces MRGPRX2-dependent degranulation, histamine release, prostaglandin D2 production, and cytokine expression. Pharmacological inhibition and western blot analysis reveal that CST activates multiple downstream G protein-dependent signaling pathways in an MRGPRX2-dependent manner. These findings demonstrate that CST promotes wound healing and bacterial clearance by activating mast cells through Mrgprb2, thereby enhancing antimicrobial peptide production. Our study positions CST as a promising mast cell-targeting immunotherapeutic candidate for treating antibiotic-resistant skin infections.