Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury

The STING pathway and its induction of autophagy initiate a potent immune defense response upon the recognition of pathogenic DNA. However, this protective response is minimal, as STING activation worsens organ damage, and abnormal autophagy is observed during progressive sepsis. Whether and how the STING pathway affects autophagic flux during sepsis-induced acute lung injury (sALI) are currently unknown. Here, we demonstrate that the level of circulating mtDNA and degree of STING activation are increased in sALI patients. Furthermore, STING activation was found to play a pivotal role in mtDNA-mediated lung injury by evoking an inflammatory storm and disturbing autophagy. Mechanistically, STING activation interferes with lysosomal acidification in an interferon (IFN)-dependent manner without affecting autophagosome biogenesis or fusion, aggravating sepsis. Induction of autophagy or STING deficiency alleviated lung injury. These findings provide new insights into the role of STING in the regulatory mechanisms behind extrapulmonary sALI.

Automated summary

The STING pathway and its induction of autophagy play a crucial role in immune defense response against pathogenic DNA, but excessive activation of STING can exacerbate organ damage. Increased circulating mtDNA levels and STING activation in sALI patients contribute to lung injury by triggering an inflammatory response and disrupting autophagy. STING activation interferes with lysosomal acidification in an IFN-dependent manner, worsening sepsis.