UC San Diego

The goal of tissue repair is to restore the protective barrier function of the skin upon injuries or microorganism infection, and the process relies on a tightly orchestrated system of signaling pathways. The expression of caspase-8, an essential factor in apoptotic signaling cascade, has been reported to play a crucial role mediating wound healing responses. The downregulation of caspase-8 in epidermis recapitulates inflammation and proliferation caused by wounding. Immune cell recruitment and epidermal hyperproliferation cumulatively instigate the expansion of caspase-8 null epidermis. This phenomenon is triggered by the paracrine signaling of interleukin-1 alpha. The secretion of IL-1 [alpha] is induced by NLRP3 inflammasome, which is a multiprotein complex coordinating the innate immune system. The assembly of NLRP3 inflammasome is the key step for immediate response of inflammation, but the mechanism mediating caspase-1, which is the critical component of NLRP3 inflammasome, is still a mystery. Here we demonstrate that the increased expression of pro-caspase-1 in wound repair process is the limiting factor to coordinate cutaneous inflammation and skin stem cell proliferation regulated by IL-1 [alpha], and pro-caspase-1 is transcriptionally regulated by nuclear factor [kappa]B (NF[kappa]B). Inhibition of NF[kappa]B significantly reduces the increased pro-caspase -1 and also prevents the release of IL-1 [alpha] in caspase-8 knockout and wounded skin. Next we investigated what the primary clue is to initiate the NF[kappa]B- caspase-1 pathway. Interestingly, we unveiled that the organization of microtubule is involved in the activation of NF[kappa]B, and caspase-8 colocalizes with microtubule filaments in primary keratinocytes. Furthermore, the disorganized microtubule cooresponding to the downregulation of caspase-8 induces the elevation of pro- caspase-1, and stabilization of microtubule in caspase-8 null epidermis inhibits the secretion of IL-1 [alpha]. Our findings reveal the intricate mechanism regulating inflammation and proliferation by caspase-8 during tissue regeneration, and it provides insights into the cause and the molecular therapy of many inflammatory disorders and cancer