Metabolic dysfunction–associated steatotic liver disease is a chronic inflammatory manifestation of metabolic disease that is strongly associated with increased cardiovascular mortality. During disease progression, liver sinusoidal endothelial cells (LSECs) undergo capillarization, a phenotypic shift characterized by loss of fenestrae and downregulation of LSEC specialized markers. While capillarization is recognized as a hallmark of disease severity, the extent of LSEC molecular heterogeneity and their dynamic interactions with immune cells and inflammatory cues remain incompletely defined.
Using a mouse model of metabolic inflammation, we identified an immunogenic LSEC subpopulation that emerges during disease progression. This population is defined by LSEC dedifferentiation, acquisition of antigen‑presenting traits, and spatial association with capillarized hepatic vessels. Diseased LSECs exhibit an enhanced chemokine secretome that promotes immune cell extravasation in extrahepatic vascular beds. Ligand–receptor analyses revealed altered crosstalk between immunogenic LSECs with T follicular helper cells and B cells, consistent with activation of adaptive immune responses. In vivo knockdown targeting this vascular–immune axis attenuated hepatic inflammation and fibrosis signatures. Clinically, patients with liver fibrosis were associated with elevated circulating autoantibodies directed against LSEC antigens.
This work expands the concept of LSEC capillarization from a structural remodeling hallmark to an active immunomodulatory process, uncovering vascular–immune mechanisms that shape liver inflammation and systemic vasculopathy, and informing strategies for disease stratification and intervention.