Role of CC chemokine receptor 9 in the progression of murine and human non-alcoholic steatohepatitis

J Hepatol. 2021 Mar;74(3):511-521. doi: 10.1016/j.jhep.2020.09.033. Epub 2020 Oct 8.


Background & aims: The number of patients with non-alcoholic steatohepatitis (NASH) is increasing globally. Recently, specific chemokine receptors have garnered interest as therapeutic targets in NASH. This is the first report to examine the role of the C-C chemokine receptor 9 (CCR9)/C-C chemokine receptor ligand 25 (CCL25) axis, and to reveal its therapeutic potential in NASH.

Methods: Patients with biopsy-proven non-alcoholic liver disease (NAFLD) were recruited and their serum and hepatic chemokine expression was examined. Furthermore, wild-type (WT) and Ccr9-/- mice were fed a high-fat high-cholesterol (HFHC) diet for 24 weeks to establish NASH.

Results: Serum CCL25, and hepatic CCR9 and CCL25 expression levels were increased in patients with NASH compared to healthy volunteers. Furthermore, Ccr9-/- mice were protected from HFHC diet-induced NASH progression both serologically and histologically. Flow cytometry and immunohistochemistry analysis showed that CCR9+CD11b+ inflammatory macrophages accumulated in the inflamed livers of HFHC diet-fed mice, while the number was reduced in Ccr9-/- mice. Consistent with human NASH livers, CCR9 was also expressed on hepatic stellate cells (HSCs) in mice with NASH, while CCR9-deficient HSCs showed less fibrogenic potential in vitro. Administration of a CCR9 antagonist hampered further fibrosis progression in mice with NASH, supporting its potential clinical application. Finally, we showed that CCR9 blockade attenuated the development of NAFLD-related hepatocellular carcinoma in HF diet-fed mice injected with diethylnitrosamine.

Conclusions: These results highlight the role of the CCR9/CCL25 axis on macrophage recruitment and fibrosis formation in a murine NASH model, providing new insights into therapeutic strategies for NASH.

Lay summary: Herein, we show that a specific chemokine axis involving a receptor (CCR9) and its ligand (CCL25) contributes to the progression of non-alcoholic steatohepatitis and carcinogenesis in humans and mice. Furthermore, treatment with a CCR9 antagonist ameliorates the development of steatohepatitis and holds promise for the treatment of patients with non-alcoholic steatohepatitis.

Keywords: CCL25/TECK; CCR9 antagonist; Hepatic stellate cell; Hepatocellular carcinoma; Liver fibrosis; NAFLD; NASH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Carcinoma, Hepatocellular / complications*
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / prevention & control
  • Case-Control Studies
  • Chemokines, CC / blood
  • Chemokines, CC / metabolism
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Disease Progression*
  • Female
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Liver / pathology
  • Liver Neoplasms / complications*
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / prevention & control
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / blood*
  • Non-alcoholic Fatty Liver Disease / complications*
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / pathology
  • Receptors, CCR / antagonists & inhibitors
  • Receptors, CCR / genetics
  • Receptors, CCR / metabolism*
  • Sulfonamides / administration & dosage
  • Treatment Outcome


  • CC chemokine receptor 9
  • CCL25 protein, human
  • CCX282-B
  • Ccl25 protein, mouse
  • Chemokines, CC
  • Receptors, CCR
  • Sulfonamides