biostudies-literatureDong XHoward Hughes Medical InstituteNIAID NIH HHSNINDS NIH HHSNIAMS NIH HHSNIGMS NIH HHS1645-1662.e7https://www.ebi.ac.uk/biostudies/studies/S-EPMC9474599biostudies-literatureUnknown55(9)Healthy skin maintains a diverse microbiome and a potent immune system to fight off infections. Here, we discovered that the epithelial-cell-derived antimicrobial peptides defensins activated orphan G-protein-coupled receptors (GPCRs) Mrgpra2a/b on neutrophils. This signaling axis was required for effective neutrophil-mediated skin immunity and microbiome homeostasis. We generated mutant mouse lines lacking the entire Defensin (Def) gene cluster in keratinocytes or Mrgpra2a/b. Def and Mrgpra2 mutant animals both exhibited skin dysbiosis, with reduced microbial diversity and expansion of Staphylococcus species. Defensins and Mrgpra2 were critical for combating S. aureus infections and the formation of neutrophil abscesses, a hallmark of antibacterial immunity. Activation of Mrgpra2 by defenImmunityKeratinocyte-derived defensins activate neutrophil-specific receptors Mrgpra2a/b to prevent skin dysbiosis and bacterial infection.PMC9474599R01 AR074846R37 NS054791R01 AI146177P30 AR079200R21 AI167047T32 AR074920R01 AR077007T32 GM136577R01 AR070116R01 AR069502R01 AR073665Youn CGoff LLu WDong XSypek EIWang GPundir PGarza LAAlphonse MPLay MArcher NKVasavda COrtines RVLimjunyawong NKothari RDikeman DKim BSWang YMiller LSfalseKeratinocyte-derived defensins activate neutrophil-specific receptors Mrgpra2a/b to 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 the epithelial-cell-derived antimicrobial peptides defensins activated orphan G-protein-coupled receptors (GPCRs) Mrgpra2a/b on neutrophils. This signaling axis was required for effective neutrophil-mediated skin immunity and microbiome homeostasis. We generated mutant mouse lines lacking the entire Defensin (Def) gene cluster in keratinocytes or Mrgpra2a/b. Def and Mrgpra2 mutant animals both exhibited skin dysbiosis, with reduced microbial diversity and expansion of Staphylococcus species. Defensins and Mrgpra2 were critical for combating S. aureus infections and the formation of neutrophil abscesses, a hallmark of antibacterial immunity. Activation of Mrgpra2 by defen2022-01-01T00:00:00Z2022 Sep2026-05-28T01:22:38.896Z2024-11-13T21:39:56.492ZS-EPMC94745993588223610.1016/j.immuni.2022.06.021