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

Rei Morikawa, Nobuhiro Nakamoto, Takeru Amiya, Po sung Chu, Yuzo Koda, Toshiaki Teratani, Takahiro Suzuki, Yutaka Kurebayashi, Akihisa Ueno, Nobuhito Taniki, Kentaro Miyamoto, Akihiro Yamaguchi, Shunsuke Shiba, Tadashi Katayama, Kosuke Yoshida, Yoshiaki Takada, Rino Ishihara, Hirotoshi Ebinuma, Michiie Sakamoto, Takanori Kanai

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)511-521
Number of pages11
JournalJournal of Hepatology
Volume74
Issue number3
DOIs
Publication statusPublished - 2021 Mar

Keywords

  • CCL25/TECK
  • CCR9 antagonist
  • Hepatic stellate cell
  • Hepatocellular carcinoma
  • Liver fibrosis
  • NAFLD
  • NASH

ASJC Scopus subject areas

  • Hepatology

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