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

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.
Authors	Qinjie Liu, Jie Wu, Xufei Zhang, Xuanheng Li, Xiuwen Wu, Yun Zhao, Jianan Ren
Journal	Cell death & disease (Cell Death Dis) Vol. 12 Issue 7 Pg. 673 (07 03 2021) ISSN: 2041-4889 [Electronic] England
PMID	34218252 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Autophagy-Related Proteins Cell-Free Nucleic Acids DNA, Mitochondrial Inflammation Mediators Membrane Proteins STING1 protein, human Sting1 protein, mouse Interferons
Topics	Acute Lung Injury (etiology, genetics, metabolism, pathology) Animals Autophagy Autophagy-Related Proteins (metabolism) Cell-Free Nucleic Acids (blood, genetics) DNA, Mitochondrial (blood, genetics) Disease Models, Animal Humans Hydrogen-Ion Concentration Inflammation Mediators (metabolism) Interferons (metabolism) Lung (metabolism, pathology) Lysosomes (genetics, metabolism, pathology) Membrane Proteins (genetics, metabolism) Mice Mice, Inbred C57BL Mice, Knockout RAW 264.7 Cells Sepsis (complications, microbiology)

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