CDDO-imidazolide ameliorates sepsis-mediated alveolar macrophage pyroptosis by promoting mitophagy via the Nrf2/PINK1 pathway

Abstract Background NLRP3 inflammasome-mediated alveolar macrophage pyroptosis has been reported in promoting sepsis-related acute respiratory distress syndrome(ARDS).The nuclear factor E2-related factor (Nrf2) is involved in regulating NLRP3 inflammasome activation and pyroptosis. CDDO-imidazole (CDDO-Im), a forceful Nrf2 activator, in sepsis-related ARDS is lacking and its underling mechanism are still unclear. In this study, we aim to investigate the effect of CDDO-Im on lung protection and explored its underlying molecular mechanisms. Methods CDDO-Im (10, 50, 100nM) and 3-methyladenine (3-MA) were individually added into LPS and ATP stimulated alveolar macrophage cell line J774A.1 pyroptosis model. The Nrf2- / - and Nrf2+ /+ mice were administered intraperitoneally with CDDO-Im (3µmol/kg body weight) before cecal ligation perforation surgery. Results In vitro studies we found that NLRP3 inflammasome activation mediated pyroptosis and slightly PINK1-meditaed mitophagy in alveolar macrophage cell line J774A.1 cells after LPS and ATP exposure. The autophagy inhibitor 3-methyladenine (3-MA) significantly aggravated NLRP3 inflammasome-mediated pyroptosis in J774A.1 cells by blocking PINK1-meditaed mitophagy. CDDO-Im obviously prevented NLRP3 inflammasome-mediated pyroptosis and HMGB1 release by Nrf2 pathway to enhance mitophagy in J774A.1 cells after LPS and ATP exposure. In vivo studies we found CDDO-Im significantly alleviated sepsis-related ARDS by blocking NLRP3 inflammasome activation via Nrf2 pathway to enhance mitophagy. Conclusion Our results demonstrate that CDDO-Im exhibits prominent lung protective role owing to its Nrf2 activation and mitophagy-enhancing properties, which provide a new insight into the strategies of ARDS clinical prevention and treatment.