Caspase-14 recognizes and processes IL-1β in epithelial cells to drive anti-bacterial IgG production

Caspases-mediated processing of cytokines coordinates cell-autonomous defenses and induction of systemic inflammation 1. While caspase-1 processes IL-1{beta} and IL-18 2-5, human caspase-4 processes IL-18 mainly in monocytes 6. Caspase-14 is an exception, specializing in epidermal differentiation7,8, yet no cytokine target has been firmly established for caspase-14. Here, we report that recognition and IL-1{beta} maturation of IL-1{beta} by caspase-14 in epithelial cells determined anti-bacterial humoral immunity against Yersina pseudotuberculosis (Y. pseudotuberculosis) infection. Upon TAK1 inhibition by YopJ, activated caspase-8 cleaved caspase-14 at Asp 146, generating an active 16-kDa fragment, whose exposed pocket directly interacted with and cleaves pro-IL-1{beta} at Cys132. Moreover, conditional knock-out of caspase-14 in epithelial cells or knock-in of a caspase-inactive caspase-14C136A mutant impaired Y. pseudotuberculosis induced IL-1{beta} production and eliminated the total anti-Y. pseudotuberculosis IgG production, leading to uncontrolled Y. pseudotuberculosis infection. Thus, our findings establish caspase-14 as a processor of IL-1{beta} in epithelial cells to propel anti-bacterial humoral immunity, providing insights into the inflammation and vaccine development.