RGD Reference Report - Chemokine receptors CCR2 and CX3CR1 regulate skin fibrosis in the mouse model of cytokine-induced systemic sclerosis. - Rat Genome Database

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Chemokine receptors CCR2 and CX3CR1 regulate skin fibrosis in the mouse model of cytokine-induced systemic sclerosis.

Authors: Arai, M  Ikawa, Y  Chujo, S  Hamaguchi, Y  Ishida, W  Shirasaki, F  Hasegawa, M  Mukaida, N  Fujimoto, M  Takehara, K 
Citation: Arai M, etal., J Dermatol Sci. 2013 Mar;69(3):250-8. doi: 10.1016/j.jdermsci.2012.10.010. Epub 2012 Oct 24.
RGD ID: 9479741
Pubmed: PMID:23142052   (View Abstract at PubMed)
DOI: DOI:10.1016/j.jdermsci.2012.10.010   (Journal Full-text)

BACKGROUND: Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive accumulation of extracellular matrix (ECM), and develop under the influence of certain cytokines. We previously established a mouse model of skin fibrosis induced by exogenous application of cytokines. We have revealed that both the number of macrophages and the levels of macrophage chemoattractant protein-1 (MCP-1) mRNA positively correlate with the extent of skin fibrosis. Macrophages can be divided into two subsets, the first expressing CCR2, and the second expressing CX3CR1. OBJECTIVE: To elucidate the role of skin infiltrating macrophages based on CCR2 and CX3CR1 in this cytokine-induced murine fibrosis model. METHODS: We examined the amounts of collagen deposited in granulation tissues, the numbers of macrophages and the levels of several mRNA in wild type (WT) mice, CCR2(-/-) mice, and CX3CR1(-/-) mice during injections of transforming growth factor-beta (TGF-beta) followed by injections of connective tissue growth factor (CTGF). RESULTS: TGF-beta injection increased the expressions of MCP-1, fractalkine, CCR2 and CX3CR1 mRNA in WT mice. The overproduction of collagen induced by TGF-beta was significantly reduced by CCR2 deficiency, while collagen contents induced by CTGF were restored to wild-type levels. In contrast, overproduction of collagen in CX3CR1-deficient mice decreased nearly 50% by both TGF-beta and CTGF stimulations. CONCLUSION: The involvement of CCR2/MCP-1 interaction (CCR2-dependent loop) was during the TGF-beta phase. In contrast, the fractalkine/CX3CR1 interaction contributes to the initiation of fibrosis by TGF-beta and its maintenance by CTGF. Collectively, two subsets of macrophages both cooperatively and independently play important roles in the development of fibrosis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
systemic scleroderma  ISOCcr2 (Mus musculus)9479741; 9479741 RGD 
systemic scleroderma  ISOCx3cr1 (Mus musculus)9479741; 9479741 RGD 
systemic scleroderma  IMP 9479741; 9479741 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccr2  (C-C motif chemokine receptor 2)
Cx3cr1  (C-X3-C motif chemokine receptor 1)

Genes (Mus musculus)
Ccr2  (C-C motif chemokine receptor 2)
Cx3cr1  (C-X3-C motif chemokine receptor 1)

Genes (Homo sapiens)
CCR2  (C-C motif chemokine receptor 2)
CX3CR1  (C-X3-C motif chemokine receptor 1)


Additional Information