Junctional adhesion molecule C mediates leukocyte adhesion to rheumatoid arthritis synovium

Abstract

OBJECTIVE: Leukocyte infiltration into the rheumatoid arthritis (RA) synovium is a multistep process in which leukocytes leave the bloodstream and invade the synovial tissue (ST). Leukocyte transendothelial migration and adhesion to RA ST requires adhesion molecules on the surface of endothelial cells and RA ST fibroblasts. This study was undertaken to investigate the role of junctional adhesion molecule C (JAM-C) in mediating leukocyte recruitment and retention in the RA joint. METHODS: Immunohistologic analysis was performed on RA, osteoarthritis (OA), and normal ST samples to quantify JAM-C expression. Fibroblast JAM-C expression was also analyzed using Western blotting, cell surface enzyme-linked immunosorbent assay, and immunofluorescence. To determine the role of JAM-C in leukocyte retention in the RA synovium, in vitro and in situ adhesion assays and RA ST fibroblast transmigration assays were performed. RESULTS: JAM-C was highly expressed by RA ST lining cells, and its expression was increased in OA ST and RA ST endothelial cells compared with normal ST endothelial cells. JAM-C was also expressed on the surface of OA ST and RA ST fibroblasts. Furthermore, we demonstrated that myeloid U937 cell adhesion to both OA ST and RA ST fibroblasts and to RA ST was dependent on JAM-C. U937 cell migration through an RA ST fibroblast monolayer was enhanced in the presence of neutralizing antibodies against JAM-C. CONCLUSION: Our results highlight the novel role of JAM-C in recruiting and retaining leukocytes in the RA synovium and suggest that targeting JAM-C may be important in combating inflammatory diseases such as RA

Comparative genome-wide gene expression analysis of rheumatoid arthritis and osteoarthritis

“…Impairment of neutrophil Fc gamma R cytosolic signaling in active RA could reflect a receptor signaling defect with potential effects on Fc-mediated functions or a defect in calcium ion homeostasis within these cells (Goulding and Guyre, 1992). Leukocyte transendothelial migration and adhesion to RA synovial tissue requires adhesion molecules at the surface of endothelial cells and RA synovial tissue fibroblasts, and the junctional adhesion molecule C may be crucial for mediating leukocyte recruitment and retention in the RA joint (Rabquer et al, 2008).…”

Junctional adhesion molecule-A is abnormally expressed in diffuse cutaneous systemic sclerosis skin and mediates myeloid cell adhesion

“…We performed immunohistological staining on cryosections from SSc and normal skin, as described previously 10. Goat anti-human JAM-A antibody (R&D Systems, Minneapolis, Minnesota, USA) was used as a primary antibody.…”

“…Cell lysis and western blotting were performed as described 10. Membranes were probed with anti-human JAM-A antibody (R&D Systems).…”

Angiogenesis and vasculogenesis in rheumatoid arthritis

“…Junctional adhesion molecules (JAMs) including JAM-A, JAM-B and JAM-C have also been implicated in the adhesive processes underlying RA, as well as in synovial angiogenesis [59,60].…”