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. In this study, we discovered that epithelium-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 two mutant mouse lines, Defensin conditional knockout (Def cKO, K14-cre; Def fl/fl) in which the entire Def gene cluster is conditionally deleted from keratinocytes, and Mrgpra2 double knockout (Mrgpra2 dKO). We used high-throughput RNA sequencing to evaluate the whole transcriptomes of WT and mutant animals' skin under naive condition and 24 hours post-S. aureus infection. Disruption of defensin-Mrgpra2 signaling caused reduction of a network of pro-inflammatory and antibacterial gene expression. This study demonstrates the importance of epithelial-neutrophil signaling via the defensin-Mrgpra2 axis in maintaining healthy skin ecology and promoting antibacterial host defense. A total of 36 samples' Total RNA were purified from naïve or S. aureus infected skin of WT, Def cKO, and Mrgpra2 genoype dKO mice, with 6 biological replicates each.