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

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.

Automated summary

In this study, we found that Pseudomonas aeruginosa-induced acute lung injury (ALI) poses a serious risk to public health, but the underlying pathological mechanisms are unclear. We demonstrated that PA-mediated epithelial necroptosis plays a crucial role in the pathogenesis. Pharmacological and genomic inhibition of necroptosis signaling pathway improved PA-induced ALI and pulmonary inflammation. We further revealed the involvement of NLRP3 inflammasome in this process. Mechanistic investigations showed a crosstalk between inflammasome activation and necroptosis, where MLKL-dependent necroptosis signaling promoted changes in mitochondrial membrane potential and release of reactive oxygen species, triggering inflammasome activation. Antioxidants, such as Mito-TEMPO, were shown to restrain inflammasome activation in the epithelium, leading to a reduction in PA-induced pulmonary inflammation. Overall, our findings highlight the critical role of necroptosis-triggered NLRP3 inflammasome in PA-mediated lung injury, suggesting it as a potential therapeutic target for pulmonary inflammation.