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

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of cutaneous infections, underscoring the need for alternative therapeutic strategies. Catestatin, 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 catestatin expression is upregulated in MRSA-infected skin wounds and that topical catestatin application significantly 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, catestatin treatment leads to Mrgprb2-dependent suppression of inflammatory cytokine production and leukocyte infiltration, alongside upregulation of the antimicrobial peptide Defb14. In human mast cells, catestatin induces MRGPRX2-dependent degranulation, histamine release, prostaglandin D2 production, and cytokine expression. Pharmacological inhibition and western blot analysis reveal that catestatin activates multiple downstream G protein-dependent signaling pathways in an MRGPRX2-dependent manner. These findings demonstrate that catestatin promotes bacterial clearance by activating mast cells through Mrgprb2, thereby enhancing antimicrobial peptide production. Our study positions catestatin as a promising mast cell-targeting immunotherapeutic candidate for treating antibiotic-resistant skin infections.