Activated autophagy drives the adaptive response to LPS-evoked lung pyroptosis in adolescent mice

The disease of lipopolysaccharide (LPS)-induced acute lung injury (ALI) is prevalent among clinical respiratory patients. The LPS adaptive response is a phenomenon whereby prior exposure to a low dose of LPS results in insensitivity to a subsequent high-dose challenge. However, the LPS adaptive response and its mechanism in mice with LPS-induced ALI remains limited. In this study, CD-1 male mice received a low-dose LPS (0.1 mg/kg) pretreatment for 24 h before high-dose LPS (5 mg/kg) challenge. Pretreatment with low-dose LPS mitigates the effects of high-dose LPS-induced lung pyroptosis and ALI. Low-dose LPS pretreatment also blocked high-dose LPS-induced activation of NLRC4 inflammasome in the lung. Interestingly, low-dose LPS pretreatment further increased the level of autophagy-related proteins in the lung with high-dose LPS treatment, suggesting that autophagy was further activated after low-dose LPS pretreatment. It is also important to note that 3-methyladenine is a specific inhibitor of autophagy, blocks the adaptive response to LPS-evoked pyroptosis and ALI. Inversely, rapamycin, an autophagy inducer, promotes adaptive response to LPS-evoked pyroptosis and ALI. Mechanistically, activated autophagy drives the adaptive response to LPS-evoked lung pyroptosis in mice via promoting p62-dependent degradation of NLRC4. Collectively, our results indicate that low-dose LPS pretreatment activates autophagy to degrade NLRC4 by p62 dependent manner, thereby protecting against pyroptosis and ALI induced by high-dose of LPS.