Neutrophil extracellular traps activate hepatic stellate cells and monocytes via NLRP3 sensing in alcohol-induced acceleration of MASH fibrosis

作者：Mrigya Babuta, Caroline Morel, Marcelle de Carvalho Ribeiro, Charles D. Calenda, Martí Ortega‐Ribera, Prashanth Thevkar Nagesh, Christopher Copeland, Yuan Zhuang, Yanbo Wang, Yeonhee Cho, Radhika Joshi, Veronika Brezáni, Danielle Hawryluk, Aditi Ashish Datta, Jeeval Mehta, Imad Nasser, Gyöngyi Szabó · 发表于：Gut · 年份：2024 · DOI：10.1136/gutjnl-2023-331447 · 被引用次数：96 · 研究领域：Liver physiology and pathology、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Liver Disease Diagnosis and Treatment

OBJECTIVE: Alcohol use in metabolic dysfunction-associated steatohepatitis (MASH) is associated with an increased risk of fibrosis and liver-related death. Here, we aimed to identify a mechanism through which repeated alcohol binges exacerbate liver injury in a high fat-cholesterol-sugar diet (MASH diet)-induced model of MASH. DESIGN: C57BL/6 mice received either chow or the MASH diet for 3 months with or without weekly alcohol binges. Neutrophil infiltration, neutrophil extracellular traps (NETs) and fibrosis were evaluated. RESULTS: We found that alcohol binges in MASH increase liver injury and fibrosis. Liver transcriptomic profiling revealed differential expression of genes involved in extracellular matrix reorganisation, neutrophil activation and inflammation compared with alcohol or the MASH diet alone. Alcohol binges specifically increased NET formation in MASH livers in mice, and NETs were also increased in human livers with MASH plus alcohol use. We discovered that cell-free NETs are sensed via Nod-like receptor protein 3 (NLRP3). Furthermore, we show that cell-free NETs in vitro induce a profibrotic phenotype in hepatic stellate cells (HSCs) and proinflammatory monocytes. In vivo, neutrophil depletion using anti-Ly6G antibody or NET disruption with deoxyribonuclease treatment abrogated monocyte and HSC activation and ameliorated liver damage and fibrosis. In vivo, inhibition of NLRP3 using MCC950 or NLRP3 deficiency attenuated NET formation, liver injury and fibrosi...