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Myeloid TGF-b signaling shapes liver macrophage heterogeneity and metabolic liver disease pathogenesis

ABSTRACT: Cellular heterogeneity of innate immune cells such as macrophages is a hallmark of metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis. The mechanisms shaping liver macrophage heterogeneity and polarization during disease progression remain poorly understood. Here we identified TGF-b signaling as a critical regulator of the bifurcate maturation of TREM2+ and NEGR1+ macrophages in MASH liver. Myeloid-specific inactivation of Tgfbr1 in mice exacerbated diet-induced MASH pathologies, including hepatocyte injury, inflammation, and liver fibrosis. Mechanistically, ablation of TGF-b signaling in myeloid cells resulted in diminished TREM2+ macrophages and a marked expansion of NEGR1+ macrophages in the liver. The latter is characterized by induction of gene signatures associated with inflammasome activation, cytokine signaling, cellular senescence, and immunosuppression. The expansion of NEGR1+ macrophage contributes to effector T cell exhaustion, thereby facilitating the development of MASH-associated hepatocellular carcinoma in Tgfbr1-deficient mice. Together, these studies uncover myeloid TGF-b signaling as a crucial factor within the liver microenvironment that shapes liver macrophage heterogeneity and functional polarization during MASH pathogenesis and the development of MASH-associated liver cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE273661 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:Background: Immune cell-driven inflammation is a key mediator of metabolic dysfunction-associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P1) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages into the liver. Methods: The LyzMCre approach was used to generate myeloid cell-specific knockout mice, termed S1pr1MKO. Littermate S1pr1loxp/loxp mice were used as wild-type (WT) controls. MASH was established by feeding mice a high-fat, fructose, and -cholesterol (FFC) diet for 24 weeks which leads to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry. Results: Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in FFC-fed S1pr1MKO compared to WT. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of FFC-fed S1pr1MKO mice compared to WT. Gene ontology pathway analysis revealed a significant suppression of the peroxisome proliferator-activated receptor gamma (PPARγ) and mitogen activated protein kinase (MAPK) pathways in S1pr1MKO consistent with attenuated MASH in mice. Conclusion: Deletion of S1P1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.

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Myeloid TGF-b signaling shapes liver macrophage heterogeneity and metabolic liver disease pathogenesis

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