PDF(Pubmed)
Abstract：
Binge drinking in obese patients positively correlates with accelerated liver damage and liver-related death. However, the underlying mechanism and the effect of alcohol use on the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) remain unexplored. Here, we show that short-term feeding of a metabolic-dysfunction-associated steatohepatitis (MASH) diet plus daily acute alcohol binges for three days induce liver injury and activation of the NLRP3 inflammasome. We identify that a MASH diet plus acute alcohol binges promote liver inflammation via increased infiltration of monocyte-derived macrophages, neutrophil recruitment, and NET release in the liver. Our results suggest that both monocyte-derived macrophages and neutrophils are activated via NLRP3, while the administration of MCC950, an NLRP3 inhibitor, dampens these effects.In this study, we reveal important intercellular communication between hepatocytes and neutrophils. We discover that the MASH diet plus alcohol induces IL-1β via NLRP3 activation and that IL-1β acts on hepatocytes and promotes the production of CXCL1 and LCN2. In turn, the increase in these neutrophils recruits chemokines and causes further infiltration and activation of neutrophils in the liver. In vivo administration of the NLRP3 inhibitor, MCC950, improves the early phase of MetALD by preventing liver damage, steatosis, inflammation, and immune cells recruitment.
摘要：
肥胖患者的暴饮暴食与加速的肝损伤和肝相关死亡呈正相关。然而,潜在的机制和饮酒对代谢功能障碍相关性脂肪变性肝病(MASLD)进展的影响仍未被研究.这里,我们表明,短期喂养代谢功能障碍相关脂肪性肝炎(MASH)饮食加上每日急性饮酒3天,会导致肝损伤和NLRP3炎性体的激活.我们发现，MASH饮食加急性酒精中毒通过增加单核细胞衍生的巨噬细胞浸润促进肝脏炎症，中性粒细胞募集，和网络在肝脏中释放。我们的结果表明，单核细胞衍生的巨噬细胞和中性粒细胞都通过NLRP3被激活，而NLRP3抑制剂MCC950的给药，抑制这些影响。在这项研究中,我们揭示了肝细胞和中性粒细胞之间重要的细胞间通讯。我们发现MASH饮食加酒精通过NLRP3激活诱导IL-1β，IL-1β作用于肝细胞并促进CXCL1和LCN2的产生。反过来,这些中性粒细胞的增加会招募趋化因子，并导致肝脏中中性粒细胞的进一步浸润和激活。NLRP3抑制剂的体内给药，MCC950，通过预防肝损伤改善MetALD的早期阶段，脂肪变性,炎症,和免疫细胞募集。
