Role of CC chemokine receptor 9 in the progression of murine and human non-alcoholic steatohepatitis.
J Hepatol
; 74(3): 511-521, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-33038434
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. LAYSUMMARY:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
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Progressão da Doença
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Receptores CCR
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Hepatopatia Gordurosa não Alcoólica
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Neoplasias Hepáticas
Tipo de estudo:
Observational_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Hepatol
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão