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Open Access Research article

Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis

Bradley J Rabquer1*, Pei-Suen Tsou1, Yong Hou1, Eshwar Thirunavukkarasu1, G Kenneth Haines2, Ann J Impens1, Kristine Phillips1, Bashar Kahaleh3, James R Seibold14 and Alisa E Koch15

Author Affiliations

1 Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Dr., Ann Arbor, MI 48109, USA

2 Department of Pathology, Yale University, 200 South Frontage Rd., New Haven, CT 06510, USA

3 Department of Medicine, University of Toledo, 3000 Arlington Ave., Toledo, OH 43614, USA

4 Current address: Scleroderma Research Consultants, LLC, 97 Deer Run, Avon, CT 06001, USA

5 Department of Veterans Affairs, VA Medical Service, 2215 Fuller Rd., Ann Arbor, MI 48105, USA

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Arthritis Research & Therapy 2011, 13:R18  doi:10.1186/ar3242

Published: 8 February 2011

Abstract

Introduction

Systemic sclerosis (SSc) is characterized by fibrosis and microvascular abnormalities including dysregulated angiogenesis. Chemokines, in addition to their chemoattractant properties, have the ability to modulate angiogenesis. Chemokines lacking the enzyme-linked receptor (ELR) motif, such as monokine induced by interferon-γ (IFN-γ) (MIG/CXCL9) and IFN-inducible protein 10 (IP-10/CXCL10), inhibit angiogenesis by binding CXCR3. In addition, CXCL16 promotes angiogenesis by binding its unique receptor CXCR6. In this study, we determined the expression of these chemokines and receptors in SSc skin and serum.

Methods

Immunohistology and enzyme-linked immunosorbent assays (ELISAs) were used to determine chemokine and chemokine receptor expression in the skin and serum, respectively, of SSc and normal patients. Endothelial cells (ECs) were isolated from SSc skin biopsies and chemokine and chemokine receptor expression was determined by quantitative PCR and immunofluorescence staining.

Results

Antiangiogenic IP-10/CXCL10 and MIG/CXCL9 were elevated in SSc serum and highly expressed in SSc skin. However, CXCR3, the receptor for these chemokines, was decreased on ECs in SSc vs. normal skin. CXCL16 was elevated in SSc serum and increased in SSc patients with early disease, pulmonary arterial hypertension, and those that died during the 36 months of the study. In addition, its receptor CXCR6 was overexpressed on ECs in SSc skin. At the mRNA and protein levels, CXCR3 was decreased while CXCR6 was increased on SSc ECs vs. human microvascular endothelial cells (HMVECs).

Conclusions

These results show that while the expression of MIG/CXCL9 and IP-10/CXCL10 are elevated in SSc serum, the expression of CXCR3 is downregulated on SSc dermal ECs. In contrast, CXCL16 and CXCR6 are elevated in SSc serum and on SSc dermal ECs, respectively. In all, these findings suggest angiogenic chemokine receptor expression is likely regulated in an effort to promote angiogenesis in SSc skin.