Lipid Associated Macrophages' Promotion of Fibrosis Resolution during MASH regression requires TREM2

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 sub- populations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression associated macrophages (RAM) 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 sub-populations. Trem2 is expressed in two macrophage sub- populations: (i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and (ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct MF sub-population emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage sub-population during MASH, they decreased during regression. LAM was the dominant macrophage sub-type 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 (hCLS). TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression, but also for effective regression of inflammation and fibrosis. TREM2+ MF 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 co-ordination with other cell- types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid-handling and collagen degradation.