Priming Inflammation through Type I Interferon Pathway: The Aggravating Role of ADAR1 Down-Regulation in Sepsis-Induced Lung Injury

Abstract

Abstract Objectives and design: The objective of this prospective experimental study is to investigate the role and underlying mechanism of ADAR1 knockdown in regulating inflammation and lung injury in mice with sepsis. Subjects: ADAR1 TM-inducible knockout mice(ADAR1flox/flox;ER−Cre+). Treatment: To achieve ADAR1 knockdown, intraperitoneal injections of tamoxifen or vehicle corn oil were administered to 6- to 8-week-old mice on day 1 and day 3. After 2 days of TM treatment, sepsis was induced in mice by administering intraperitoneal injections of lipopolysaccharide (LPS). Methods ADAR1 inducible knockout mice and bone marrow-derived macrophages (BMDMs) were used for this study. Tamoxifen treatment was administered to induce ADAR1 knockdown, and LPS was injected to induce sepsis in mice. The cecal ligation and puncture model was also used. Results ADAR1 increase worsened sepsis in mice and patients. Knockdown led to increased mortality and lung injury, as well as elevated levels of inflammatory cytokines. Conclusions ADAR1 is crucial in regulating inflammation and lung injury in sepsis. Decrease of ADAR1 expression level activates type I interferon signaling pathways and increase inflammatory response, reducing LPS resistance. This study highlights ADAR1's essential role in maintaining immune inflammatory response.