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    Staphylococcus epidermidis-derived protease Esp mediates proteolytic activation of pro-IL-1beta in human keratinocytes. The Journal of investigative dermatology 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, SE induces the release of mature IL-1beta. IL-1beta 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-1beta. Typically, processing and release of IL-1beta are associated with inflammasome assembly and activation of the protease caspase-1. Here we report that bacterial challenge of keratinocytes with SE induced the release of mature IL-1beta in a caspase-1-independent manner. Instead, the SE -derived serine protease Esp was identified as a pro-IL-1beta processing factor leading to a proteolytic maturation of active IL-1beta. Esp production and secretion by various SE strains correlated with their capacity to induce release of mature IL-1beta in human primary keratinocytes. Reconstitution of Esp-lacking SE strains with Esp enhanced their capacity to induce IL-1beta release in keratinocytes and skin. Intracellular abundance of pro-IL-1beta and cytotoxic effects of SE suggest release of pro-IL-1beta during injury followed by extracellular Esp-mediated processing to mature IL-1beta. These findings provide further insights into how a skin commensal interacts with keratinocytes to activate cutaneous host innate defense. 10.1016/j.jid.2022.04.010