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A signaling pathway mediating wound healing responses

Abstract

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

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