NETs Promote Inflammatory Injury by Activating cGAS-STING Pathway in Acute Lung Injury

Abstract

Acute respiratory distress syndrome (ARDS) threatens the survival of critically ill patients, the mechanisms of which are still unclear. Neutrophil extracellular traps (NETs) released by activated neutrophils play a critical role in inflammatory injury. We investigated the role of NETs and the underlying mechanism involved in acute lung injury (ALI). We found a higher expression of NETs and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) in the airways, which was reduced by Deoxyribonuclease I (DNase I) in ALI. The administration of the STING inhibitor H-151 also significantly relieved inflammatory lung injury, but failed to affect the high expression of NETs in ALI. We isolated murine neutrophils from bone marrow and acquired human neutrophils by inducing HL-60 to differentiate. After the PMA interventions, exogenous NETs were obtained from such extracted neutrophils. Exogenous NETs intervention in vitro and in vivo resulted in airway injury, and such inflammatory lung injury was reversed upon degrading NETs with or inhibiting cGAS-STING with H-151 as well as siRNA STING. In conclusion, cGAS-STING participates in regulating NETs-mediated inflammatory pulmonary injury, which is expected to be a new therapeutic target for ARDS/ALI.

Genetically Engineered Cellular Nanovesicle as Targeted DNase I Delivery System for the Clearance of Neutrophil Extracellular Traps in Acute Lung Injury

“…This reduction in neutrophil infiltration may be attributed to the suppression of the cGAS‐STING pathway, a DNA‐sensing pathway that regulates the expression of inflammatory chemokines and cytokines. [ 30 ] A recent study has also demonstrated that the inhibition of the cGAS‐STING pathway reduces neutrophil infiltration in the ALI mouse model. [ 31 ] These results demonstrate that pharmacological inhibition of NETs by DCNV can attenuate the inflammatory response in the ALI mouse model.…”

Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury

“…Pulmonary ALI was induced by intratracheal injection of Lipopolysaccharide (LPS) (10 mg/kg, from Pseudomonas aeruginosa 27316, Sigma-Aldrich, USA, L9143) dissolved in 50 μl sterile PBS. Additionally, we used intraperitoneal injection of LPS (25 mg/kg) to construct sepsis-related ARDS, known as extra-pulmonary ALI ( 18 ). The mice enjoyed free access to food and water and were monitored until sacrificed 24 h after the treatment.…”

The cGAS-STING pathway in cardiovascular diseases: from basic research to clinical perspectives

“…Neutrophils are one of the most common effector cells of the innate immune system and play an instrumental role in cardiovascular pathophysiology, in addition to their anti-infective function [ 134 , 135 ]. Neutrophil extracellular traps (NETs) released by activated neutrophils play a crucial role in inflammatory injury [ 136 ]. Numerous recent studies have shown that NETs are associated with CVDs, such as AS [ 137 ], myocarditis [ 138 ], and MI [ 139 ], which may be related to the unique cell death program of neutrophils called "NETosis,” “NETosis” releases granules, cytoplasmic guanosine-conjugated chromatin, and bactericidal proteins to form a reticulum during cell death that plays a crucial role in host defense, autoimmunity, and blood coagulation [ 140 ].…”