2. Academic Validation
  3. Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury

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

  • Cell Death Dis. 2021 Jul 3;12(7):673. doi: 10.1038/s41419-021-03961-9.
Qinjie Liu  # 1,  Jie Wu  # 2,  Xufei Zhang 3,  Xuanheng Li 4,  Xiuwen Wu 5,  Yun Zhao 6,  Jianan Ren 7 8 9 10
Affiliations

Affiliations

  • 1 Research Institute of General Surgery, Jinling Hospital, Medical school of Nanjing University, Nanjing, China.
  • 2 Department of General Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China.
  • 3 Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China.
  • 4 Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, China.
  • 5 Research Institute of General Surgery, Jinling Hospital, Nanjing, China. [email protected].
  • 6 Department of General Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • 7 Research Institute of General Surgery, Jinling Hospital, Medical school of Nanjing University, Nanjing, China. [email protected].
  • 8 Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China. [email protected].
  • 9 Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, China. [email protected].
  • 10 Research Institute of General Surgery, Jinling Hospital, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 34218252 DOI: 10.1038/s41419-021-03961-9
Abstract

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.

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