Staphylococcus epidermidis-Derived Protease Esp Mediates Proteolytic Activation of Pro‒IL-1β in Human Keratinocytes.

The Gram-positive bacterium Staphylococcus epidermidis (SE) is an abundant skin commensal. It plays an important role in cutaneous defense by activation of IL-1 signaling. In keratinocytes (KCs), SE induces the release of mature IL-1β. IL-1β serves as an important cytokine of host defense. It contains an N-terminal prodomain that has to be cleaved off to generate active mature IL-1β. Typically, the processing and release of IL-1β are associated with inflammasome assembly and activation of the protease caspase-1. In this study, we report that the bacterial challenge of KCs with SE induced the release of mature IL-1β in a caspase-1‒independent manner. Instead, the SE-derived serine protease Esp was identified as a pro‒IL-1β‒processing factor leading to a proteolytic maturation of active IL-1β. Esp production and secretion by various SE strains correlated with their capacity to induce the release of mature IL-1β in human primary KCs. Reconstitution of Esp-lacking SE strains with Esp enhanced their capacity to induce IL-1β release in KCs and skin. Intracellular abundance of pro‒IL-1β and cytotoxic effects of SE suggest a release of pro‒IL-1β during injury, followed by extracellular Esp-mediated processing to mature IL-1β. These findings provide further insights into how a skin commensal interacts with KCs to activate cutaneous host innate defense.