The proadhesive phenotype of systemic sclerosis skin promotes myeloid cell adhesion via ICAM-1 and VCAM-1.
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.
Department of Internal Medicine, University of Michigan Medical School, AnnArbor, MI, USA. brabquer@med.umich.edu
Bradley J
BJ
Rabquer
Yong
Y
Hou
Francesco
F
Del Galdo
G
G
Kenneth Haines
Michele L
ML
Gerber
Sergio A
SA
Jimenez
James R
JR
Seibold
Alisa E
AE
Koch
D000071443:12E7 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D016022:Case-Control Studies; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000378:metabolism; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D022423:Myeloid Cells / Q000473:pathology*; D012595:Scleroderma, Systemic / Q000473:pathology*; D012867:Skin / Q000473:pathology*; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism*; D062765:Junctional Adhesion Molecule B
D000071443:12E7 Antigen; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D018799:Intercellular Adhesion Molecule-1; D019010:Vascular Cell Adhesion Molecule-1; C061828:CD99 protein, human; C411887:JAM2 protein, human; D062765:Junctional Adhesion Molecule B; C448000:JAM3 protein, human