RGD Reference Report - CCR1 and CCR5 promote hepatic fibrosis in mice. - Rat Genome Database

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CCR1 and CCR5 promote hepatic fibrosis in mice.

Authors: Seki, Ekihiro  De Minicis, Samuele  Gwak, Geum-Youn  Kluwe, Johannes  Inokuchi, Sayaka  Bursill, Christina A  Llovet, Josep M  Brenner, David A  Schwabe, Robert F 
Citation: Seki E, etal., J Clin Invest. 2009 Jul;119(7):1858-70.
RGD ID: 14401743
Pubmed: PMID:19603542   (View Abstract at PubMed)
PMCID: PMC2701864   (View Article at PubMed Central)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CCR5HumanExperimental Liver Cirrhosis treatmentISOCcr5 (Mus musculus) RGD 
CCR5HumanExperimental Liver Cirrhosis  ISOCcr5 (Mus musculus)mRNA,protein:increased expression:liverRGD 
Ccr5RatExperimental Liver Cirrhosis treatmentISOCcr5 (Mus musculus) RGD 
Ccr5RatExperimental Liver Cirrhosis  ISOCcr5 (Mus musculus)mRNA,protein:increased expression:liverRGD 
Ccr5MouseExperimental Liver Cirrhosis treatmentIMP  RGD 
Ccr5MouseExperimental Liver Cirrhosis  IEP mRNA,protein:increased expression:liverRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccr5  (C-C motif chemokine receptor 5)

Genes (Mus musculus)
Ccr5  (C-C motif chemokine receptor 5)

Genes (Homo sapiens)
CCR5  (C-C motif chemokine receptor 5)


Additional Information