| The fractalkine receptor CX₃CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. | |
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MedLine Citation:
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PMID: 21038415 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Chemokines modulate inflammatory responses that are prerequisites for organ fibrosis upon liver injury. Monocyte-derived hepatic macrophages are critical for the development, maintenance, and resolution of hepatic fibrosis. The specific role of monocyte-associated chemokine (C-X3-C motif) receptor 1 (CX₃CR1) and its cognate ligand fractalkine [chemokine (C-X3-C motif) ligand 1)] in liver inflammation and fibrosis is currently unknown. We examined 169 patients with chronic liver diseases and 84 healthy controls; we found that CX₃CL1 is significantly up-regulated in the circulation upon disease progression, whereas CX₃CR1 is down-regulated intrahepatically in patients with advanced liver fibrosis or cirrhosis. To analyze the functional relevance of this pathway, two models of experimental liver fibrosis were applied to wild-type (WT) and CX₃CR1-deficient mice. Fractalkine expression was induced upon liver injury in mice, primarily in hepatocytes and hepatic stellate cells. CX₃CR1(-/-) animals developed greater hepatic fibrosis than WT animals with carbon tetrachloride-induced and bile duct ligation-induced fibrosis. CX₃CR1(-/-) mice displayed significantly increased numbers of monocyte-derived macrophages within the injured liver. Chimeric animals that underwent bone marrow transplantation revealed that CX₃CR1 restricts hepatic fibrosis progression and monocyte accumulation through mechanisms exerted by infiltrating immune cells. In the absence of CX₃CR1, intrahepatic monocytes develop preferentially into proinflammatory tumor necrosis factor-producing and inducible nitric oxide synthase-producing macrophages. CX₃CR1 represents an essential survival signal for hepatic monocyte-derived macrophages by activating antiapoptotic bcl2 expression. Monocytes/macrophages lacking CX₃CR1 undergo increased cell death after liver injury, which then perpetuates inflammation, promotes prolonged inflammatory monocyte infiltration into the liver, and results in enhanced liver fibrosis. CONCLUSION: CX₃CR1 limits liver fibrosis in vivo by controlling the differentiation and survival of intrahepatic monocytes. The opposing regulation of CX₃CR1 and fractalkine in patients suggests that pharmacological augmentation of this pathway may represent a possible therapeutic antifibrotic strategy. |
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Authors:
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Karlin Raja Karlmark; Henning W Zimmermann; Christoph Roderburg; Nikolaus Gassler; Hermann E Wasmuth; Tom Luedde; Christian Trautwein; Frank Tacke |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 52 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-01 Completed Date: 2010-11-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 1769-82 Citation Subset: IM |
Affiliation:
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Department of Medicine III, University Hospital Aachen, Aachen, Germany. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Actins
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genetics Alanine Transaminase / genetics Animals Bone Marrow Transplantation Cell Differentiation / drug effects* Crosses, Genetic Flow Cytometry Glyceraldehyde-3-Phosphate Dehydrogenases / genetics Humans Leukocytes / cytology*, physiology Liver / cytology*, drug effects Liver Cirrhosis / prevention & control* Mice Mice, Inbred C57BL Mice, Knockout Monocytes / cytology*, drug effects Polymerase Chain Reaction Receptors, Chemokine / deficiency, therapeutic use* |
| Chemical | |
Reg. No./Substance:
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0/Actins; 0/CX3CR1 protein, human; 0/Cx3cr1 protein, mouse; 0/Receptors, Chemokine; 0/alpha-smooth muscle actin, mouse; EC 1.2.1.-/Glyceraldehyde-3-Phosphate Dehydrogenases; EC 2.6.1.2/Alanine Transaminase |
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