ADAR1 protects pulmonary macrophages from sepsis-induced pyroptosis and lung injury through miR-21/A20 signaling

Acute lung injury is a serious complication of sepsis with high morbidity and mortality. Pyroptosis is a proinflammatory form of programmed cell death that leads to immune dysregulation and organ dysfunction during sepsis. We previously found that adenosine deaminase acting on double-stranded RNA 1 (ADAR1) plays regulatory roles in the pathology of sepsis, but the mechanism of ADAR1 in sepsis-induced pyroptosis and lung injury remains unclear. Here, we mainly investigated the regulatory effects and underlying mechanism of ADAR1 in sepsis-induced lung injury and pyroptosis of pulmonary macrophages through RNA sequencing of clinical samples, caecal ligation and puncture (CLP)-induced septic mouse models, and in vitro cellular experiments using RAW264.7 cells with lipopolysaccharide (LPS) stimulation. The results showed that pyroptosis was activated in peripheral blood mononuclear cells (PBMCs) from patients with sepsis. In the CLP-induced septic mouse model, pyroptosis was mainly activated in pulmonary macrophages. LPS-stimulated RAW264.7 cells showed significantly increased activation of the NLRP3 inflammasome. ADAR1 was downregulated in PMBCs of patients with sepsis, and overexpression of ADAR1 alleviated CLP-induced lung injury and NLRP3 inflammasome activation. Mechanistically, the regulatory effects of ADAR1 on macrophage pyroptosis were mediated by the miR-21/A20/NLRP3 signalling cascade. ADAR1 attenuated sepsis-induced lung injury and hindered the activation of pyroptosis in pulmonary macrophages in sepsis through the miR-21/A20/NLRP3 axis. Our study highlights the role of ADAR1 in protecting pulmonary macrophages against pyroptosis and suggests targeting ADAR1/miR-21 signalling as a therapeutic opportunity in sepsis-related lung injury.