Novel mechanism reveals alveolar epithelial autophagy protects against Pseudomonas infection

Infections by the antibiotic-resistant bacterium Pseudomonas aeruginosa (P. aeruginosa) pose a significant health risk, especially for patients with weakened immune systems or chronic respiratory conditions. However, the mechanisms through which this bacterium damages lung tissues remain poorly understood, limiting effective therapeutic approaches.

In a recent study published in MedComm, a research team led by professor Guoping Li (Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu) and professor Min Wu (Wenzhou Institute, University of Chinese Academy of Sciences) unveiled an important protective mechanism involving autophagy, specifically the protein ATG5, in alveolar epithelial cells during P. aeruginosa infection.

“Our findings uniquely highlight the role of ATG5-mediated autophagy specifically within alveolar epithelial cells,” Professor Wu explained. “We demonstrated that when ATG5 is deficient, it not only exacerbates the inflammatory response but specifically enhances a distinct cell death pathway called pyroptosis. Crucially, this pyroptosis is triggered by non-canonical caspase-11 rather than classical caspase-1, leading to the cleavage and activation of gasdermin D.”

The team revealed that activated gasdermin D forms pores in alveolar epithelial cells, enabling mitochondrial DNA (mtDNA) to leak into the extracellular space. This leaked mtDNA significantly amplifies inflammation by activating macrophages through the cGAS-STING-NLRP3 signaling cascade, thereby exacerbating lung damage during infection.

Dr. Junyi Wang, the first author of the study, from Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu highlighted this critical mechanism, stating, “Our study reveals a novel link where epithelial-derived mtDNA, facilitated by gasdermin-mediated pyroptosis, dramatically enhances macrophage activation. This cross-talk substantially worsens the inflammation observed in infected lungs.”

Highlighting the clinical implications, Professor Guoping Li emphasized, “Our study sheds light on previously unrecognized molecular mechanisms of lung inflammation during bacterial infections. These findings pave the way for new therapeutic strategies targeting autophagy enhancement or inhibition of the caspase-mtDNA-cGAS-STING-NLRP3 signaling axis to control inflammation and improve patient outcomes in severe respiratory infections caused by antibiotic-resistant pathogens.”