Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2⁺ macrophages in various disease conditions, and substantial induction of TREM2⁺ NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2⁺ macrophages in disease pathogenesis.

中文翻译：

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肝脏危险信号触发 TREM2+ 巨噬细胞诱导并通过 MS4A7 依赖性炎症小体激活驱动脂肪性肝炎

代谢功能障碍相关脂肪性肝炎（MASH），以前称为非酒精性脂肪性肝炎（NASH），是代谢性脂肪肝病的晚期阶段。MASH 的致病机制集中在肝细胞损伤和肝脏微环境内随后的免疫反应。最近的研究表明 TREM2 ⁺巨噬细胞与各种疾病状况有关，并且 TREM2 ⁺ NASH 相关巨噬细胞 (NAM) 的大量诱导是代谢性肝病的标志。尽管如此，NAM 促进 MASH 发病机制的机制仍然知之甚少。在这里，我们将跨膜 4 结构域 a7 (MS4A7) 确定为 NAM 特异性致病因子，可加剧小鼠 MASH 进展。小鼠和人类 MASH 中肝脏 MS4A7 表达被强烈诱导，并且与肝损伤的严重程度相关。Ms4a7的全身和骨髓特异性消融减轻了雄性小鼠饮食诱导的 MASH 病理。我们证明，暴露于脂肪变性肝细胞损伤时释放的脂滴 (LD) 会触发 NAM 诱导，并以 MS4A7 依赖性方式加剧 MASH 相关的肝损伤。从机制上讲，MS4A7 通过直接物理相互作用驱动 NLRP3 炎症小体激活，并在肝脏微环境中塑造疾病相关的细胞状态。^{这项工作揭示了 LD-MS4A7-NLRP3 炎性体轴作为 MASH 进展的致病驱动因素，并深入了解 TREM2 +}巨噬细胞在疾病发病机制中的作用。