Neutrophil Extracellular Traps Exacerbate Liver Ischemia-Reperfusion Injury by Promoting Macrophage M1 Polarization via the cGAS-STING Pathway

Hepatic ischemia-reperfusion injury (IRI) is a serious complication during liver transplantation, which triggers a strongrepresents a significant complication in the context of liver transplantation, characterized by the induction of a robust non-specific inflammatory response throughmediated by damage-associated molecular patterns (DAMPs) and leads to, ultimately resulting in dysfunction of the transplanted liverorgan. The pathogenic pro-inflammatory (M1) polarization of hepatic macrophages is a driver of this hepatocyte injury, but the exact upstream trigger factor for this remains unclear. We investigated thecritical contributor to this hepatocellular damage; however, the precise upstream trigger remains unidentified. This study explores the potential role of neutrophil extracellular traps (NETs) as an upstream regulator of M1-type macrophage polarization. Utilizing the in vivo H-IRI mouse model alongside an in vitro macrophage co-culture system, we elucidated that the interaction between neutrophil extracellular traps (NETs) and macrophages is facilitated by the cGAS-STING signaling pathway. Our findings indicate that the double-stranded DNA generated by NETs is internalized by macrophages, subsequently activating the cytoplasmic sensor cGAS and the adaptor protein 3wSTING. This activation serves as a driver for the M1 macrophage phenotype. Our study unveils a novel and critical pathway, "NETs → cGAS-STING → M1 polarization," which plays a significant role in hepatic ischemia-reperfusion injury (HIRI). This pathway presents a promising therapeutic target for mitigating graft damage following liver transplantation.