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

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.