Neutrophil-Specific Defensin Receptors Prevent Skin Dysbiosis and Bacterial Infection

Healthy skin maintains a diverse microbiome and a potent immune system to fight off infections. Here, we discovered that epithelial cell-derived antimicrobial peptides defensins activate orphan GPCRs Mrgpra2a/b on neutrophils. This signaling axis is required for effective neutrophil-mediated skin immunity and microbiome homeostasis. We generated mutant mouse lines lacking the entire Defensin (Def) gene cluster or Mrgpra2a/b. Def and Mrgpra2 mutant animals both exhibited skin dysbiosis, with reduced microbial diversity and expansion of Staphylococcus species. Furthermore, we found that defensins and Mrgpra2 are critical for combatting S. aureus infections and the formation of neutrophil abscesses, a hallmark of antibacterial immunity. Activation of Mrgpra2 by defensin triggers neutrophils to release the pro-inflammatory cytokine IL-1β, which is vital for proper amplification and propagation of the antibacterial immune response. This study demonstrates the importance of epithelial-neutrophil signaling via the defensin-Mrgpra2 axis in maintaining healthy skin ecology and promoting antibacterial host defense.