CX3CL1-CX3CR1 Interaction Prevents Carbon Tetrachloride-Induced Liver Inflammation and Fibrosis in Mice
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Chronic liver disease is associated with hepatocyte injury, inflammation, and fibrosis. Chemokines and chemokine receptors are key factors for the migration of inflammatory cells such as macrophages and noninflammatory cells such as hepatic stellate cells (HSCs). The expression of CX3CR1 and its ligand, CX3CL1, is up-regulated in chronic liver diseases such as chronic hepatitis C. However, the precise role of CX3CR1 in the liver is still unclear. Here we investigated the role of the CX3CL1-CX3CR1 interaction in a carbon tetrachloride (CCl4)–induced liver inflammation and fibrosis model. CX3CR1 was dominantly expressed in Kupffer cells in the liver. In contrast, the main source of CX3CL1 was HSCs. Mice deficient in CX3CR1 showed significant increases in inflammatory cell recruitment and cytokine production [including tumor necrosis factor α (TNF-α); monocyte chemoattractant protein 1; macrophage inflammatory protein 1β; and regulated upon activation, normal T cell expressed, and secreted (RANTES)] after CCl4 treatment versus wild-type (WT) mice. This suggested that CX3CR1 signaling prevented liver inflammation. Kupffer cells in CX3CR1-deficient mice after CCl4 treatment showed increased expression of TNF-α and transforming growth factor β and reduced expression of the anti-inflammatory markers interleukin-10 (IL-10) and arginase-1. Coculture experiments showed that HSCs experienced significantly greater activation by Kupffer cells from CCl4-treated CX3CR1-deficient mice versus WT mice. Indeed, augmented fibrosis was observed in CX3CR1-deficient mice versus WT mice after CCl4 treatment. Finally, CX3CL1 treatment induced the expression of IL-10 and arginase-1 in WT cultured Kupffer cells through CX3CR1, which in turn suppressed HSC activation. Conclusion: The CX3CL1-CX3CR1 interaction inhibits inflammatory properties in Kupffer cells/macrophages and results in decreased liver inflammation and fibrosis. (Hepatology 2010)
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HSCs release signals such as CX3CL1 that restrain pro-fibrogenic signaling by macrophages even during ongoing injury.
“HSCs release signals such as CX3CL1 that restrain pro-fibrogenic signaling by macrophages even during ongoing injury (58, 59).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [58]
Levels of IL-10 and TGF-β expression are not necessarily coregulated during tissue repair.
“Furthermore, levels of IL-10 and TGF- expression are not necessarily coregulated during tissue repair; Mp display increased mRNA expression of IL-10 but not TGF- during chronic liver fibrosis in mice, and deficiency of the chemokine receptor CX 3 CR 1 results in reduced IL-10 but increased TGF- expression by Mp [69].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [69]
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CX3CR1+ macrophages interact with HSCs to promote HCC through CD8+ T-cell suppression
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- Authors
- Aoyama, T., Inokuchi, S., Brenner, D. A., & Seki, E.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Seki, Ekihiro
- Venue
- Hepatology
- Published
- 2010-10
- Volume
- 52
- Issue
- 4
- Pages
- 1390-1400
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC2947579
- OpenAlex
- W2097460049
- Cited by
- 211
- References
- 50
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 14 · 2023: 13 · 2022: 27 · 2021: 10 · 2020: 11 · 2019: 8 · 2018: 13 · 2017: 10 · 2016: 14 · 2015: 11 · 2014: 14 · 2013: 11 · 2012: 17
- FWCI
- 9.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (P50-AA11999, R01AA020172, P50AA011999)
- National Institute of General Medical Sciences (R01GM041804)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK085252)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- fractalkine, CX3CR1, chemokine signaling, carbon tetrachloride, liver fibrosis, liver inflammation, Kupffer cells, hepatic stellate cells, hepatic stellate cell activation, macrophage polarization, IL-10, arginase-1, TNF-α, chronic liver disease
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Carbon Tetrachloride Poisoning, Cell Movement, Kupffer Cells, Mice, Inbred C57BL, Signal Transduction, Interleukin-10, Coculture Techniques, Receptors, Chemokine, Mice, Chemokine CX3CL1, Hepatic Stellate Cells, Chemical and Drug Induced Liver Injury
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