Linked Life Data

21038415

Source:http://linkedlifedata.com/resource/pubmed/id/21038415

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2010-11-1
pubmed:abstractText
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 (CX?CR1) 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 CX?CL1 is significantly up-regulated in the circulation upon disease progression, whereas CX?CR1 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 CX?CR1-deficient mice. Fractalkine expression was induced upon liver injury in mice, primarily in hepatocytes and hepatic stellate cells. CX?CR1(-/-) animals developed greater hepatic fibrosis than WT animals with carbon tetrachloride-induced and bile duct ligation-induced fibrosis. CX?CR1(-/-) mice displayed significantly increased numbers of monocyte-derived macrophages within the injured liver. Chimeric animals that underwent bone marrow transplantation revealed that CX?CR1 restricts hepatic fibrosis progression and monocyte accumulation through mechanisms exerted by infiltrating immune cells. In the absence of CX?CR1, intrahepatic monocytes develop preferentially into proinflammatory tumor necrosis factor-producing and inducible nitric oxide synthase-producing macrophages. CX?CR1 represents an essential survival signal for hepatic monocyte-derived macrophages by activating antiapoptotic bcl2 expression. Monocytes/macrophages lacking CX?CR1 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: CX?CR1 limits liver fibrosis in vivo by controlling the differentiation and survival of intrahepatic monocytes. The opposing regulation of CX?CR1 and fractalkine in patients suggests that pharmacological augmentation of this pathway may represent a possible therapeutic antifibrotic strategy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1527-3350
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
52
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1769-82
pubmed:meshHeading
pubmed-meshheading:21038415-Actins, pubmed-meshheading:21038415-Alanine Transaminase, pubmed-meshheading:21038415-Animals, pubmed-meshheading:21038415-Bone Marrow Transplantation, pubmed-meshheading:21038415-Cell Differentiation, pubmed-meshheading:21038415-Crosses, Genetic, pubmed-meshheading:21038415-Flow Cytometry, pubmed-meshheading:21038415-Glyceraldehyde-3-Phosphate Dehydrogenases, pubmed-meshheading:21038415-Humans, pubmed-meshheading:21038415-Leukocytes, pubmed-meshheading:21038415-Liver, pubmed-meshheading:21038415-Liver Cirrhosis, pubmed-meshheading:21038415-Mice, pubmed-meshheading:21038415-Mice, Inbred C57BL, pubmed-meshheading:21038415-Mice, Knockout, pubmed-meshheading:21038415-Monocytes, pubmed-meshheading:21038415-Polymerase Chain Reaction, pubmed-meshheading:21038415-Receptors, Chemokine
pubmed:year
2010
pubmed:articleTitle
The fractalkine receptor CX?CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes.
pubmed:affiliation
Department of Medicine III, University Hospital Aachen, Aachen, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't