Targeted Cx43 therapeutics reduce NLRP3 inflammasome activation in rat burn injury

Burns are dynamic injuries characterized by an initial zone of necrosis that progresses to compromise surrounding tissue. Acute inflammation and cell death are two main factors contributing to burn progression. These processes are modulated by Connexin43 (Cx43) hemichannels and gap junctions in burns and chronic wounds. Particularly, Cx43-mediated ATP release may interact with the P2X7 receptor to activate the NLRP3 inflammasome pathway. This study used a deep partial thickness rat burn model to evaluate the effect of Cx43 antisense oligodeoxynucleotides (Cx43asODN) or the Cx43 hemichannel blocker Tonabersat for the inhibition of inflammasome activation and their use as potential treatments for burn injury. Using immunofluorescence analysis, our data showed that Cx43asODN or Tonabersat reduced Cx43 hemichannel and gap junction expression. Concomitantly, they marginally and transiently reduced P2X7 expression and inflammasome complex assembly and inflammation. Quantitative analysis using H&E, Masson's trichrome & Picrosirus Red revealed reduced epidermal thickness and improved collagen preservation in treated burn wounds. Collectively, our findings suggest a possible involvement of the Cx43-mediated NLRP3 inflammasome pathway via P2X7 activation in early burn wound healing. This indicates that targeting Cx43 may have a potential therapeutic effect to improve healing outcomes.