Sustained Secretion of the Antimicrobial Peptide S100A7 Is Mediated by the Wound Healing Machinery

Antimicrobial peptides (AMPs) are the body’s natural innate immune defense against a spectrum of pathogenic insults and provide an attractive strategy towards combating the growing problem of antibiotic resistant microorganisms. The prophylactic use of AMPs is contingent upon understanding the regulatory mechanisms governing the release of AMPs from intracellular stores, which occurs via the non-conventional secretory pathway. Analysis of S100A7 (Psoriasin), an abundant AMP in the skin, from its endogenous stores within differentiated keratinocytes has revealed an unexpected biphasic secretory response to bacterial exposure. The core components regulating S100A7 secretion are NFκB/p38MAPK, caspase-1 and IL-1α. The early activation of this core machinery is mediated by toll-like receptor signaling, whereas the chronic response is regulated by the wound-healing machinery mediated by Caspase-8 downregulation. Interestingly, in inflammatory skin diseases in which S100A7 is excessively released, there is a concomitant downregulation of caspase-8, indicating that these pathological scenarios are commandeering the normal wound healing response. These results highlight the potential benefits of targeting intracellular wound healing pathways as a means of exerting control over the release of AMPs from the skin in both homeostatic and disease conditions.