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

Qinjie Liu,Xufei Zhang,Jianan Ren,Yun Zhao,Xuanheng Li,Jie Wu,Xiuwen Wu

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.

Highlights

Sepsis is a life-threatening condition and a major global health challenge [1]
The results showed a deeper color to derived from the GSE66890 dataset [11], which showed that the represent more severe ROS injury, and time- and concentrationlevel of cGAS and stimulator of interferon genes (STING) expression were increased in patients dependent mitochondrial DNA (mtDNA)-induced oxidative injury in WT Bone marrow-derived macrophages (BMDMs) was with sepsis-induced acute lung injury (ALI) (sALI) patients with sepsis (Fig. S1)
MtDNA-mediated STING activation impedes lysosomal acidification, aggravating disease group (Fig. 2f). These results indicate that increased circulating To identify the step in autophagy whose dysfunction is driven by the levels of mtDNA act as a key link in sALI because they activate the STING pathway, we further evaluated the initiation of autophagy, STING pathway and impair autophagy

Summary

Introduction

Sepsis is a life-threatening condition and a major global health challenge [1]. The lung is the first organ to suffer from sepsisinduced insult, which results in acute lung injury (ALI) as well as its more severe form, acute respiratory distress syndrome (ARDS) [2]. It is critical to dissect the molecular mechanisms leading to sepsis-induced ALI (sALI) and the translational implications of these findings. Numerous clinical studies have confirmed that the level of circulating mitochondrial DNA (mtDNA) is closely related to the severity and prognosis of sepsis and ARDS [2]. We have found that mtDNA plays a fundamental role in the mechanism of cellular injury and lethal sepsis by triggering the stimulator of interferon genes (STING) pathway, an intracellular DNAsensing pattern recognition receptor, leading to remote organ injury [4, 5]. A translation gap between studies of ALI due to clinical nonpulmonary insult and preclinical mtDNA-mediated immune cascade studies remains, as the mechanism underlying the development of lung injury from infection at a distant site is multifactorial and has not been well addressed

Methods

Results

Conclusion