Abstract

Background: Macrophage (MF) are recruited to the liver during MASH progression, including fibrogenic TREM2+ hepatic lipid associated MF (LAMs). However, the TREM2 receptor itself is anti-fibrotic, in that Trem2^-/- mice have more severe MASH than WT mice. Despite these recent studies, little is known about mechanisms that regulate MF function during MASH regression. We studied Trem2 expression in MF across the MF clusters during MASH regression, identified MF sub-populations that aid in MASH resolution, and investigated whether Trem2 is required for efficient MASH regression and the underlying mechanisms.

Methods: Foz (Alms1^-/-)¹ and Foz::Trem2^-/- mice on Western Diet (WD) developed MASH by 12w¹. Foz mice are hyperphagic and develop MASH on a WD. Regression was studied by switching MASH mice to normal chow for an additional 4-8w. scRNAseq elucidated MF gene signatures and pathways. In vitro experiments were performed with bone marrow derived MF (BMDM) from WT and Trem2^-/- mice.

Results: Absence of Trem2 impaired fibrosis, inflammation and steatosis resolution during MASH regression. scRNAseq revealed two Trem2-expressing MF sub-populations during MASH progression and regression in Foz+WD mice: (i) Monocyte derived MF that occupy the Kupffer cell niche (MoKC), and (ii) hepatic lipid associated MF (LAM). While MoKC was the major MF sub-population during MASH progression, it decreased during regression with reduced Trem2 expression. LAMs maintained Trem2 expression and expanded, becoming the dominant MF sub-population during regression. Within the regression livers, scRNAseq revealed that Trem2-hi MF were highly enriched in MASH-resolving pathways (extracellular matrix degradation, phagocytosis and lipid handling). Trem2-low MF, on the other hand, expressed disease worsening pathways (inflammation, cell death). While hepatic LAMs have mostly been studied in the context of MASH progression, our findings demonstrate that during regression they resemble restorative MF, with increased expression of MMPs and phagocytosis-related genes. In vitro experiments demonstrated superior collagen degradation ability by Trem2+ BMDMs compared to their Trem2- counterparts.

Conclusion: This study expands our understanding of MF heterogeneity in MASH by uncovering distinct sub-populations during regression. We highlight the significance of Trem2 in mediating MASH regression and delve into the multiple probable mechanisms through which Trem2 achieves this effect.

Animals studies: All animals received humane care according to the "Guide for the Care and Use of Laboratory Animals". Experiments were performed in accordance with the UCSD IACUC and NIH guidelines.

Human samples: Publicly available human database were mined.

Reference:¹PMID: 34062281