P. ae induced necroptosis signaling and NLRP3 inflammasome cross-talking in epithelium facilitates acute lung injury

Abstract Pseudomonas aeruginosa induced acute lung injury is such a serious risk to public health throughout the world, but the pathological regulation remains unclear. Here, we reported that P. ae mediated epithelial necroptosis leads to subsequent immune responses and plays an important role in pulmonary pathological process. Pharmacological and genomic ablation of necroptosis signaling ameliorate P. ae mediated acute lung injury and pulmonary inflammation. Our results further proved NLRP3 inflammasome to involve in P. ae induced ALI. Mechanism investigation revealed the cross-talking patterns between inflammasome activation and necroptosis signaling pathway 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 epithelial cells, resulting in a reduction in P. ae induced ALI and pulmonary inflammation. Taken together, our findings revealed that necroptosis-triggered NLRP3 inflammasome in epithelium plays a key role in P. ae mediated injury, which could be a potential therapeutic target for acute lung injury.