Cul4B up‐regulation attenuates sepsis‐induced acute lung injury by promoting NLRP3 ubiquitination and inhibiting NLRP3 inflammasome activation
Huihui Hu, Jiabei Wang, Yuqing Zhang, Chuanjie Yao, Fengzhi Zhao, Xiangkun Yuan, Feng Zhang, Zheng Xiang, Guozhen Cui, Mei Jing, Peng Yi, Yewei Sun, Gaoxiao Zhang, Yuqiang Wang, Hai‐Yan Yin, Zaijun Zhang, Wan‐Jie GuBackground and Purpose
Cullin 4B (Cul4B), a scaffold protein of CUL4B‐RING E3 ligase complex, functions primarily as a negative regulator of inflammation. This study aims to investigate its role in acute lung injury (ALI) and NLRP3 ubiquitination.
Experimental approach
Cul4B expression and distribution were examined in two sepsis‐induced ALI mouse models. Lung‐specific overexpression and myeloid‐specific Cul4B deletion were applied to evaluate its effects on lung histopathology, pulmonary inflammation, and alveolar capillary barrier dysfunction. The role of Cul4B in NLRP3 inflammasome activation was evaluated in THP‐1 cells and Cul4B‐deficient BMDMs. Cul4B‐NLRP3 interaction and Cul4B‐mediated NLRP3 ubiquitination were determined. The involvement of Cul4B in MN‐08‐mediated ALI protection and inflammasome suppression was also investigated.
Key results
Cul4B was significantly downregulated in lung tissues of sepsis‐induced ALI mice. Pulmonary overexpression of Cul4B attenuated lung injury and inflammation, whereas myeloid‐specific deletion of Cul4B exacerbated epithelial barrier damage and inflammatory responses, along with enhanced Nigericin‐induced NLRP3 inflammasome activation. Cul4B was shown to interact with both endogenous and exogenous NLRP3 and suppressed NLRP3 inflammasome activation by promoting NLRP3 ubiquitination. MN‐08, a small molecule previously reported to alleviate lipopolysaccharide (LPS)‐induced ALI, was found to upregulate Cul4B expression and inhibit NLRP3 inflammasome activation by promoting NLRP3 ubiquitination.
Conclusions and implications
Upregulating Cul4B promotes NLRP3 ubiquitination, thereby inhibiting inflammasome activation and mitigating pulmonary epithelial barrier dysfunction and inflammation in ALI. Cul4B emerges as a potential therapeutic target, and these findings provide new insights into the mechanism by which MN‐08 protects against sepsis‐induced ALI.