CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis

JCI Insight. 2017 Nov 16;2(22):e92902. doi: 10.1172/jci.insight.92902.


Although recent evidence has pointed to the role of organ- and pathogenesis-specific macrophage subsets, it is still unclear which subsets are critically involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Using melanocortin-4 receptor-deficient (MC4R-KO) mice fed Western diet (WD), which exhibit liver phenotypes similar to those of human NASH, we found a histological structure, termed hepatic crown-like structure (hCLS), in which CD11c+ macrophages surround dead/dying hepatocytes, a prominent feature of NASH. Here, we demonstrate that hCLS-constituting macrophages could be a novel macrophage subset that drives hepatocyte death-triggered liver fibrosis. In an "inducible NASH model," hepatocyte death induces hCLS formation and liver fibrosis sequentially in the short term. In combination with the long-term WD feeding model, we also showed that resident macrophages are a major cellular source of CD11c+ macrophages constituting hCLS, which exhibited gene expression profiles distinct from CD11c- macrophages scattered in the liver. Moreover, depletion of CD11c+ macrophages abolished hCLS formation and fibrogenesis in NASH. Our clinical data suggest the role of CD11c+ macrophages in the disease progression from simple steatosis to NASH. This study sheds light on the role of resident macrophages, in addition to recruited macrophages, in the pathogenesis of NASH.

Keywords: Fibrosis; Hepatology; Inflammation; Macrophages; Obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11c Antigen / immunology
  • CD11c Antigen / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • Fatty Liver / pathology
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Humans
  • Inflammation
  • Liver / pathology
  • Liver Cirrhosis / pathology*
  • Macrophages / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Obesity / complications
  • Receptor, Melanocortin, Type 4 / genetics
  • Receptors, CCR2


  • CD11c Antigen
  • Ccr2 protein, mouse
  • Receptor, Melanocortin, Type 4
  • Receptors, CCR2