Genetic dissection of defensin signaling in skin immunity and psoriasis 2578

Abstract Description Antimicrobial peptides (AMPs) are secreted by epithelial cells at various host-microbe interfaces to kill invading pathogens. Despite their importance, the mechanisms by which AMPs interact with microbes and the host immune system remain understudied due to the lack of genetic tools. The largest family of AMPs in the mouse genome, defensins, has over 50 functionally redundant members. To overcome this problem, we generated a Defensin cluster knockout (Def cKO) mouse in which all Def genes are removed from the skin. The Def mutant animals exhibited skin microbiome dysbiosis and severe defects in anti-S.aureus immunity. Further, immune profiling using this stringent loss-of-function approach revealed that neutrophils are key target cells of defensin signaling. We identified a pair of orphan G protein-coupled receptors (GPCRs) Mrgpra2a/b as neutrophil-specific defensin receptors. Defensin-Mrgpra2 signaling was critical for combatting S. aureus infections and the formation of neutrophil abscesses, a hallmark of antibacterial immunity. In addition to antibacterial host defense, we also found that Defensin-Mrgpr signaling is involved in the inflammatory skin disease psoriasis and is responsible for severe itch. In summary, our results revealed a key epithelial-neutrophil signaling pathway via the defensin-Mrgpra2 axis. Mechanistic analysis of this new AMP-GPCR pathway could lead to improved therapies to treat infections and skin diseases related to AMP deregulation. Funding Sources Supported by 1R01DK140039 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)