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

AbstractThe 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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Role of FMS-like tyrosine kinase-3 ligand elicited dendritic cell subsets in acute lung injury in response to S. pneumoniae infection

Pneumologie ◽

10.1055/s-0030-1270373 ◽

2011 ◽

Vol 65 (02) ◽

Author(s):

C Brumshagen ◽

R Maus ◽

T Welte ◽

U Maus

Keyword(s):

Acute Lung Injury ◽

Dendritic Cell ◽

Lung Injury ◽

Tyrosine Kinase ◽

Dendritic Cell Subsets

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Role of Tilianin against Acute Lung Injury in In Vitro LPS-Induced Alveolar Macrophage Cells and an In Vivo C57BL/6 Mice Model

Journal of Environmental Pathology Toxicology and Oncology ◽

10.1615/jenvironpatholtoxicoloncol.2020035136 ◽

2020 ◽

Vol 39 (4) ◽

pp. 335-344

Author(s):

Yonghong Zhang ◽

Zhenshuai Fu

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Alveolar Macrophage ◽

Mice Model ◽

Macrophage Cells

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Leukocyte immunoglobulin-like receptor B4 deficiency exacerbates acute lung injury via NF-κB signaling in bone marrow-derived macrophages

Bioscience Reports ◽

10.1042/bsr20181888 ◽

2019 ◽

Vol 39 (6) ◽

Cited By ~ 2

Author(s):

Tao Qiu ◽

Jiangqiao Zhou ◽

Tianyu Wang ◽

Zhongbao Chen ◽

Xiaoxiong Ma ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lung Injury ◽

Lung Injury ◽

Stromal Cells ◽

Marrow Cell ◽

Marrow Transplant ◽

Cell Source ◽

Transplant Model ◽

Acute Inflammatory Disease

AbstractAcute lung injury (ALI) is an acute inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing inhibitory receptor that is implicated in various pathological processes. However, the function of LILRB4 in ALI remains largely unknown. The aim of the present study was to explore the role of LILRB4 in ALI. LILRB4 knockout mice (LILRB4 KO) were used to construct a model of ALI. Bone marrow cell transplantation was used to identify the cell source of the LILRB4 deficiency-aggravated inflammatory response in ALI. The effect on ALI was analyzed by pathological and molecular analyses. Our results indicated that LILRB4 KO exacerbated ALI triggered by LPS. Additionally, LILRB4 deficiency can enhance lung inflammation. According to the results of our bone marrow transplant model, LILRB4 regulates the occurrence and development of ALI by bone marrow-derived macrophages (BMDMs) rather than by stromal cells in the lung. The observed inflammation was mainly due to BMDM-induced NF-κB signaling. In conclusion, our study demonstrates that LILRB4 deficiency plays a detrimental role in ALI-associated BMDM activation by prompting the NF-κB signal pathway.

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H2O2 inhibits alveolar epithelial wound repair in vitro by induction of apoptosis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00177.2003 ◽

2004 ◽

Vol 287 (2) ◽

pp. L448-L453 ◽

Cited By ~ 55

Author(s):

Thomas Geiser ◽

Masanobu Ishigaki ◽

Coretta van Leer ◽

Michael A. Matthay ◽

V. Courtney Broaddus

Keyword(s):

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Cell Viability ◽

Wound Repair ◽

Wound Edge ◽

Alveolar Epithelial ◽

Induction Of Apoptosis

Reactive oxygen species (ROS) are released into the alveolar space and contribute to alveolar epithelial damage in patients with acute lung injury. However, the role of ROS in alveolar repair is not known. We studied the effect of ROS in our in vitro wound healing model using either human A549 alveolar epithelial cells or primary distal lung epithelial cells. We found that H2O2 inhibited alveolar epithelial repair in a concentration-dependent manner. At similar concentrations, H2O2 also induced apoptosis, an effect seen particularly at the edge of the wound, leading us to hypothesize that apoptosis contributes to H2O2-induced inhibition of wound repair. To learn the role of apoptosis, we blocked caspases with the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (zVAD). In the presence of H2O2, zVAD inhibited apoptosis, particularly at the wound edge and, most importantly, maintained alveolar epithelial wound repair. In H2O2-exposed cells, zVAD also maintained cell viability as judged by improved cell spreading and/or migration at the wound edge and by a more normal mitochondrial potential difference compared with cells not treated with zVAD. In conclusion, H2O2 inhibits alveolar epithelial wound repair in large part by induction of apoptosis. Inhibition of apoptosis can maintain wound repair and cell viability in the face of ROS. Inhibiting apoptosis may be a promising new approach to improve repair of the alveolar epithelium in patients with acute lung injury.

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