While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2 + macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2 + macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2 + macrophages are superior collagen degraders. Lack of TREM2 + macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.

中文翻译：

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MASH 回归期间脂质相关巨噬细胞促进纤维化消退需要 TREM2


虽然代谢功能障碍相关脂肪性肝炎 (MASH) 期间巨噬细胞的异质性已被描述，但人们对这些巨噬细胞在 MASH 消退期间的命运知之甚少。比较 MASH 进展与回归期间的巨噬细胞异质性，我们确定了对 MASH/纤维化消退至关重要的特定巨噬细胞亚群。我们阐明了定义回归相关巨噬细胞的恢复途径和基因特征，并确定了 TREM2 + 巨噬细胞在 MASH 回归过程中的重要性。肝脏驻留的库普弗细胞在 MASH 过程中丢失，并被四种不同的单核细胞衍生的巨噬细胞亚群取代。 Trem2 在两个巨噬细胞亚群中表达：i) 占据库普弗细胞生态位 (MoKC) 的单核细胞来源的巨噬细胞和 ii) 脂质相关巨噬细胞 (LAM)。在退化肝脏中，没有出现新的转录上不同的巨噬细胞亚群。然而，与 MASH 相比，回归过程中相对巨噬细胞组成发生了变化。虽然 MoKC 是 MASH 期间的主要巨噬细胞亚群，但它们在回归期间减少。 LAM 是 MASH 消退期间的主要巨噬细胞亚型，并维持 Trem2 表达。 MoKC 和 LAM 都富含疾病解决途径。 TREM2 的缺失限制了 LAM 的出现和肝冠状结构的形成。 TREM2 + 巨噬细胞在功能上不仅对于限制 MASH 纤维化进展很重要，而且对于炎症和纤维化的有效消退也很重要。 TREM2 + 巨噬细胞是优质的胶原蛋白降解剂。 TREM2+巨噬细胞的缺乏还阻碍了肝脂肪变性的消除和HSC在消退过程中的失活，这表明它们在与肝脏中其他细胞类型的代谢协调中具有重要意义。 TREM2 通过多因素机制赋予这种保护作用，包括改善吞噬作用、脂质处理和胶原蛋白降解。