Necroptosis signaling and NLRP3 inflammasome cross-talking in epithelium facilitate Pseudomonas aeruginosa mediated lung injury

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2023-03, Vol.1869 (3), p.166613-166613, Article 166613
• Main Authors: Li, Haoyang, Guan, Jieying, Chen, Jiaqian, Sun, Weimin, Chen, Honglv, Wen, Yuhuan, Chen, Qile, Xie, Shiyun, Zhang, Xueyan, Tao, Ailin, Yan, Jie
• Format: Article
• Language: English
• Subjects: Acute lung injury; Acute Lung Injury - drug therapy; Epithelium; Humans; Inflammasome; Inflammasomes; Mito-TEMPO; Necroptosis; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; Pneumonia; Pseudomonas aeruginosa
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2022.166613

Pseudomonas aeruginosa induced acute lung injury is such a serious risk to public health, but the pathological regulation remains unclear. Here, we reported that PA mediated epithelial necroptosis plays an important role in pathological process. Pharmacological and genomic ablation of necroptosis signaling ameliorate PA mediated ALI and pulmonary inflammation. Our results further proved NLRP3 inflammasome to involve in the process. Mechanism investigation revealed the cross-talking between inflammasome activation and necroptosis that MLKL-dependent necroptosis signaling promotes the change of mitochondrial membrane potential for the release of reactive oxygen species (ROS), which is the important trigger for functional inflammasome activation. Furthermore, antioxidants such as Mito-TEMPO was confirmed to significantly restrain inflammasome activation in epithelium, resulting in a reduction in PA induced pulmonary inflammation. Taken together, our findings revealed that necroptosis-triggered NLRP3 inflammasome in epithelium plays a crucial role in PA mediated injury, which could be a potential therapeutic target for pulmonary inflammation. •Recently, although there is an amount of research just focus on ALI/ ARDS pathophysiological analysis, the development of therapies based on specific molecular targets are still lacking.•Cross-talking between necroptosis and inflammasome in epithelium promotes pathological damage of ALI.•ROS inhibitor Mito-TEMPO blocks inflammasome to alleviate inflammation of ALI, which could be a potential therapeutic target for acute lung injury.