Neutrophil Recruitment via Hepatocyte IL-1α Drives NETs-Mediated AIM2 Hepatocyte Apoptosis in Alcohol-associated steatohepatitis.

Abstract

Alcohol-associated steatohepatitis (ASH) represents a critical stage in the progression of Alcohol-associated liver disease (ALD), characterized by extensive hepatocellular steatosis, immune cell infiltration, and a poor therapeutic response. Neutrophils play a central role in the inflammatory landscape of ASH, with their hepatic accumulation strongly correlating with disease severity. Although studies have demonstrated that neutrophil depletion attenuates liver injury, the precise mechanisms underlying neutrophil-mediated hepatocellular damage remain poorly defined. Neutrophil extracellular traps (NETs), web-like DNA structures released during NETosis, have emerged as key effectors in sterile inflammation and may exacerbate liver injury beyond their antimicrobial functions. In this study, we employed the Binge-Gao mouse model to explore the involvement of NETs in ethanol-induced liver injury. Our findings revealed that ethanol exposure led to significant hepatic neutrophil infiltration and NET formation. Stressed hepatocytes released damage-associated molecular patterns (DAMPs), particularly interleukin-1 alpha (IL-1α), which activated Toll-like receptor 9 (TLR9) on neutrophils, thereby enhancing NET generation. NET components subsequently activated the cytosolic DNA sensor AIM2 (absent in melanoma 2) in hepatocytes, triggering apoptosis. This cascade illustrates a previously unrecognized immune axis linking ethanol-damaged hepatocytes, NET-producing neutrophils, and DNA-sensing death pathways.