Rheumatology Advance Access originally published online on May 13, 2009
Rheumatology 2009 48(7):734-740; doi:10.1093/rheumatology/kep091
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The proadhesive phenotype of systemic sclerosis skin promotes myeloid cell adhesion via ICAM-1 and VCAM-1
1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 2Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, 3Department of Pathology, Yale University, New Haven, CT and 4Department of Veterans Affairs, VA Medical Service, Ann Arbor, MI, USA.
Correspondence to: Bradley J. Rabquer, 109 Zina Pitcher Drive, 4418 BSRB, Ann Arbor, MI 48109-2200, USA. E-mail: brabquer{at}med.umich.edu
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Abstract |
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Objective. SSc is characterized by microvascular abnormalities and leucocyte infiltration. Previous studies have suggested a proadhesive phenotype in SSc skin, but the functional consequences of this phenotype are not fully understood. Molecules known to mediate leucocyte adhesion include those present at intracellular junctions, such as junctional adhesion molecule-B (JAM-B), JAM-C and CD99, as well as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). The aim of this study was to examine adhesive interactions in SSc skin.
Methods. The expression of JAM-B, JAM-C, CD99, ICAM-1 and VCAM-1 in SSc skin was determined by immunohistology and cell surface ELISA. Myeloid U937 cell–SSc dermal fibroblast adhesion assays or in situ adhesion assays to SSc skin were performed.
Results. JAM-C and CD99 expression on endothelial cells (ECs) in SSc skin was decreased compared with expression on normal ECs. CD99 was overexpressed on mononuclear cells in SSc skin and on SSc dermal fibroblasts. Neutralizing ICAM-1 inhibited the binding of U937 cells to SSc dermal fibroblasts. In addition, blocking both ICAM-1 and VCAM-1 inhibited U937 cell adhesion to either proximal (less involved) or distal (more involved) SSc skin.
Conclusions. These studies show that JAM-C and CD99 are aberrantly expressed in SSc skin. However, these adhesion molecules do not mediate myeloid cell–SSc skin adhesion. In contrast, we demonstrate an important role for ICAM-1 and VCAM-1 in the retention of myeloid cells in SSc skin, suggesting that targeting these molecules may be useful SSc therapies.
KEY WORDS: Systemic sclerosis, Adhesion molecules, Junctional adhesion molecules, VCAM-1, ICAM-1
*Bradley J. Rabquer and Yong Hou contributed equally to this work.
Submitted 3 November 2008;
revised version accepted 20 March 2009.
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