Cigarette smoke-induced caspase-12 nuclear translocation compromises oral mucosal defense via RIP2 and NF-κB signaling.

Cigarette smoking is a major environmental risk factor that compromises oral mucosal immunity; however, the mechanisms underlying smoke-induced epithelial dysfunction remain poorly defined. In this study, we identify cigarette smoke-induced nuclear accumulation of caspase-12 as a previously unrecognized event associated with dysregulation of epithelial innate immune responses. Analyses of clinical oral leukoplakia tissues and an active smoking rat model revealed leukoplakia-like epithelial alterations accompanied by enhanced Candida albicans colonization, together with marked nuclear enrichment of caspase-12, NF-κB p65, and RIP2. In immortalized human oral epithelial Leuk-1 cells, exposure to cigarette smoke extract (CSE) induced a concentration-dependent increase in nuclear caspase-12, NF-κB p65, and RIP2, supporting a direct effect of cigarette smoke on epithelial immune signaling. Silencing of caspase-12 attenuated CSE-induced nuclear localization of NF-κB p65 and altered RIP2 distribution. Importantly, caspase-12 knockdown restored epithelial antimicrobial function, as evidenced by increased secretion of the antimicrobial peptides hBD1 and hBD3 and enhanced antifungal activity of epithelial culture supernatants against Candida albicans under CSE exposure. Collectively, these findings indicate that caspase-12 nuclear accumulation contributes to cigarette smoke-induced impairment of epithelial innate immunity.