An Important Role of the SDF-1/CXCR4 Axis in Chronic Skin Inflammation

Inflammatory angiogenesis and vascular remodeling play key roles in the chronic inflammatory skin disease psoriasis, but little is known about the molecular mediators of vascular activation. Based on the reported elevated mRNA levels of the angiogenic chemokine stromal cell-derived factor-1 (SDF-1)...

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Vydáno v:PloS one Ročník 9; číslo 4; s. e93665
Hlavní autoři: Zgraggen, Silvana, Huggenberger, Reto, Kerl, Katrin, Detmar, Michael
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Public Library of Science 01.04.2014
Public Library of Science (PLoS)
Témata:
Aminoquinolines - therapeutic use
Analysis
Angiogenesis
Animal models
Animals
Biology and Life Sciences
Blood vessels
Care and treatment
CD11b antigen
CD4 antigen
CD8 antigen
Chemokine CXCL12 - physiology
Chemokines
Chemotaxis
Chronic Disease
CXCR4 protein
Dermatitis
Dermatitis - drug therapy
Dermatitis - physiopathology
Diagnosis
Disease
Imiquimod
Inflammation
Inhibition
Lymphatic system
Lymphocytes
Lymphocytes T
Macrophages
Medicine and Health Sciences
Mice
Mice, Inbred C57BL
mRNA
Neovascularization, Pathologic
Pharmaceutical sciences
Psoriasis
Receptors, CXCR4 - physiology
Rheumatoid arthritis
Risk factors
Rodents
SDF-1 protein
Skin
Skin diseases
Splenocytes
Systematic review
Transgenic mice
Up-Regulation
Vascular endothelial growth factor
ISSN:1932-6203, 1932-6203
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Shrnutí:Inflammatory angiogenesis and vascular remodeling play key roles in the chronic inflammatory skin disease psoriasis, but little is known about the molecular mediators of vascular activation. Based on the reported elevated mRNA levels of the angiogenic chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 in psoriasis, we investigated the relevance of the SDF-1/CXCR4 axis in two experimental models of chronic psoriasis-like skin inflammation. The cutaneous expression of both SDF-1 and CXCR4 was upregulated in the inflamed skin of K14-VEGF-A transgenic mice and in imiquimod-induced skin inflammation, with expression of CXCR4 by blood vessels and macrophages. Treatment with the CXCR4 antagonist AMD3100 potently inhibited skin inflammation in both models, associated with reduced inflammatory angiogenesis and inflammatory cell accumulation, including dermal CD4+ cells and intraepidermal CD8+ T cells. Similar anti-inflammatory effects were seen after treatment with a neutralizing anti-SDF-1 antibody. In vitro, inhibition of CXCR4 blocked SDF-1-induced chemotaxis of CD11b+ splenocytes, in agreement with the reduced number of macrophages after in vivo CXCR4 blockade. Our results reveal an important role of the SDF-1/CXCR4 axis in skin inflammation and inflammatory angiogenesis, and they indicate that inhibition of the SDF-1/CXCR4 axis might serve as a novel therapeutic strategy for chronic inflammatory skin diseases.
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Conceived and designed the experiments: SZ MD. Performed the experiments: SZ RH KK. Analyzed the data: SZ RH. Contributed reagents/materials/analysis tools: KK. Wrote the paper: SZ MD.
Competing Interests: The authors have declared that no competing interests exist.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0093665