CCR1 and CCR5 promote hepatic fibrosis in mice
Open accessAbstract
Hepatic fibrosis develops as a response to chronic liver injury and almost exclusively occurs in a proinflammatory environment. However, the role of inflammatory mediators in fibrogenic responses of the liver is only poorly understood. We therefore investigated the role of CC chemokines and their receptors in hepatic fibrogenesis. The CC chemokines MIP-1alpha, MIP-1beta, and RANTES and their receptors CCR1 and CCR5 were strongly upregulated in 2 experimental mouse models of fibrogenesis. Neutralization of CC chemokines by the broad-spectrum CC chemokine inhibitor 35k efficiently reduced hepatic fibrosis, and CCR1- and CCR5-deficient mice displayed substantially reduced hepatic fibrosis and macrophage infiltration. Analysis of fibrogenesis in CCR1- and CCR5-chimeric mice revealed that CCR1 mediates its profibrogenic effects in BM-derived cells, whereas CCR5 mediates its profibrogenic effects in resident liver cells. CCR5 promoted hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent pathway. Both CCR5-deficient HSCs and CCR1- and CCR5-deficient Kupffer cells displayed strong suppression of CC chemokine-induced migration. Finally, we detected marked upregulation of RANTES, CCR1, and CCR5 in patients with hepatic cirrhosis, confirming activation of the CC chemokine system in human fibrogenesis. Our data therefore support a role for the CC chemokine system in hepatic fibrogenesis and suggest distinct roles for CCR1 and CCR5 in Kupffer cells and HSCs.
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Monocyte-derived macrophages stimulate HSC migration and recruitment by secreting CCL2, CCL5, and SPP1.
“Monocyte-derived macrophages also stimulate HSC migration and recruitment through the secretion of CCL2, chemokine ligand 5 (CCL5), and SPP1 (70-72).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [72]
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- Authors
- Seki, E., De Minicis, S., Gwak, G.-Y., Kluwe, J., Inokuchi, S., Bursill, C. A., Llovet, J. M., Brenner, D. A., & Schwabe, R. F.
- Affiliations
- Columbia University (US)
- University of California San Diego (US)
- University of Oxford (GB)
- Universitat de Barcelona (ES)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2009-06-15
- Volume
- 119
- Issue
- 7
- Pages
- 1858-70
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2701864
- OpenAlex
- W2055176387
- Cited by
- 431
- References
- 3
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 14 · 2023: 22 · 2022: 28 · 2021: 40 · 2020: 30 · 2019: 25 · 2018: 27 · 2017: 27 · 2016: 24 · 2015: 29 · 2014: 32 · 2013: 27 · 2012: 25
- FWCI
- 19.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Funders
- Samuel Waxman Cancer Research Foundation
- American Liver Foundation
- Pfizer
- Uehara Memorial Foundation
- University of Oxford
- Institució Catalana de Recerca i Estudis Avançats
- National Institutes of Health
- University of California, San Diego
- National Institute of General Medical Sciences (R01GM041804)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076986, R01DK076920)
- School of Medicine, University of California, San Diego
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- liver fibrosis, CCR1, CCR5, CC chemokines, MIP-1α, MIP-1β, RANTES, chemokine receptor deficiency, Kupffer cells, macrophage infiltration, PI3K signaling, redox signaling, liver cirrhosis, chimeric mice
- MeSH terms
- Animals, Cell Movement, Humans, Kupffer Cells, Liver Cirrhosis, Experimental, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Receptors, CCR5, Mice, Receptors, CCR1, CCR5 Receptor Antagonists
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