ATG16L1 restrains macrophage NLRP3 activation and alveolar epithelial cell injury during septic lung injury.

Summary

Using genetic and pharmacologic approaches, the authors show that myeloid ATG16L1 prevents a ROS–NLRP3–cGAS-STING positive feedback loop that amplifies inflammation and alveolar epithelial injury in septic lung injury. Interrupting this loop via ROS scavenging or STING inhibition mitigated injury, and ATG16L1 overexpression reduced disease severity.

Key Findings

• Myeloid ATG16L1 deficiency worsened LPS-induced septic lung injury with heightened inflammation.
• ATG16L1-deficient macrophages accumulated mitochondrial ROS, activating NLRP3; epithelial dsDNA release activated cGAS-STING, creating a positive feedback to further activate NLRP3.
• Mitochondrial ROS scavenging or STING inhibition suppressed NLRP3 activation and alleviated lung injury; ATG16L1 overexpression reduced disease severity.

Clinical Implications

Although preclinical, the data prioritize testing STING and NLRP3 pathway inhibitors and strategies to enhance macrophage autophagy (e.g., augmenting ATG16L1 function) for septic lung injury.

Limitations

• LPS-induced ALI may not fully recapitulate polymicrobial human sepsis.
• Lack of human tissue validation and no clinical trial data.

Future Directions

Validate in polymicrobial sepsis models and human samples; evaluate macrophage-targeted autophagy enhancement and STING/NLRP3 inhibitors in translational studies.