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Integrating Metabolism and Immunity | EK16


Recruited monocyte-derived macrophages regulate hepatic crown-like structure formation and liver fibrosis in NASH


Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Description

Recruited monocyte-derived macrophages regulate hepatic crown-like structure formation and liver fibrosis in NASH Sabine Daemen1,2, Li He1,2, Mandy M. Chan1,3, Brian Finck1,2, Joel D. Schilling1,2,3 1Washington University School of Medicine, St. Louis, MO; 2Department of Internal Medicine; 3Department of Pathology and Immunology Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and hepatocyte injury. In response to liver damage macrophage composition changes dramatically and is characterized by a reduction in resident Kupffer cell (KC) number and recruitment of monocyte-derived macrophages (MdMs). One subset of infiltrating MdMs turns on expression of KC-specific genes and these cells serve to replenish the resident macrophage pool (i.e. Mo-KCs). In addition to Mo-KCs, we identified two populations of Trem2-expressing recruited MdMs using single cell RNA sequencing, flow cytometry and immunofluorescence. One macrophage subset expresses Cx3cr1 and Ccr2 and the second subset expresses Cd63, Cd9, and Gpnmb, which are markers previously ascribed to lipid-associated macrophages (LAMs) in obese adipose tissue. We therefore refer to these macrophage subsets as hepatic C-LAMs and LAMs, respectively. However, the function of these recruited MdM populations in NASH pathogenesis is not well understood. To investigate this, we fed wild type and Ccr2 deficient mice a NASH-inducing diet for 4 months. In Ccr2 knockout (KO) animals, the C-LAMs failed to appear in the NASH liver and the number of macrophages expressing LAM markers was reduced. Confocal imaging revealed specific homing of C-LAMs and LAMs to macrophage aggregates referred to as hepatic crown-like structures (hCLS) and these structures were dramatically reduced in Ccr2 KO mice. Somewhat surprisingly, the loss of hCLS in Ccr2 KO mice was associated with increased liver fibrosis despite a similar degree of liver steatosis, arguing that hCLS may protect against further tissue injury. Within hCLS recruited macrophages formed tight interactions with activated hepatic stellate cells, identified by a-smooth muscle actin staining. In the absence of Ccr2, stellate cell activation was decreased without any changes in total stellate cell area, suggesting that crosstalk between (C-)LAMs and stellate cells may influence tissue remodeling in NASH. In line with this concept we also discovered that macrophages isolated from NASH livers specifically altered the proliferation and organization of primary stellate cells ex vivo. Together these data indicate that recruited MdMs play a unique role(s) in the regulation of stellate cell biology and liver fibrosis during NASH.

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