Junctional Adhesion Molecule-C Is a Soluble Mediator of Angiogenesis

Abstract

Junctional adhesion molecule-C (JAM-C) is an adhesion molecule expressed by endothelial cells (ECs) that plays a role in tight junction formation, leukocyte adhesion, and transendothelial migration. In the current study, we investigated whether JAM-C is found in soluble form and whether soluble JAM-C (sJAM-C) mediates angiogenesis. We found that JAM-C is present in soluble form in normal serum and elevated in rheumatoid arthritis (RA) serum. The concentration of sJAM-C is also elevated locally in RA synovial fluid compared with RA serum or osteoarthritis synovial fluid. sJAM-C was also present in the culture supernatant of human microvascular ECs (HMVECs) and immortalized human dermal microvascular ECs, and its concentration was increased following cytokine stimulation. In addition, sJAM-C cleavage from the cell surface was mediated in part by a disintegrin and metalloproteinases 10 and 17. In functional assays, sJAM-C was both chemotactic and chemokinetic for HMVECs and induced HMVEC tube formation on Matrigel in vitro. Neutralizing anti–JAM-C Abs inhibited RA synovial fluid–induced HMVEC chemotaxis and sJAM-C–induced HMVEC tube formation on Matrigel. sJAM-C also induced angiogenesis in vivo in the Matrigel plug and sponge granuloma models. Moreover, sJAM-C–mediated HMVEC chemotaxis was dependent on Src, p38, and PI3K. Our results show that JAM-C exists in soluble form and suggest that modulation of sJAM-C may provide a novel route for controlling pathological angiogenesis.

Differential expression of junctional adhesion molecules in different stages of systemic sclerosis

“…Increasing evidence indicates that levels of soluble endothelial adhesion molecules are increased in SSc patients and that their levels may correlate with disease activity (8, 15). Recently, increased circulating levels of sJAM‐A have been reported in hypertension and atherosclerosis (20, 43), while serum sJAM‐C levels were found to be increased in rheumatoid arthritis (44).…”

JAM-related proteins in mucosal homeostasis and inflammation

“…Proinflammatory cytokines (TNF-α and IFN-γ) induce the cleavage of the extracellular region of JAM-A and JAM-C by the disintegrin and metalloproteinases 10 and 17 (ADAM10/17) in endothelial cells. Soluble JAM-A ectodomains reduced transendothelial migration of neutrophils and endothelial cell migration [141] while soluble JAM-C promoted angiogenesis [142]. Interestingly, ADAM17 is upregulated by TNFα in the intestinal epithelium [143], and JAM-A has been reported to be released from epithelial cells [141].…”

The pathogenic role of angiogenesis in rheumatoid arthritis

“…JAM-C is also cleaved from the surface of endothelial cells by ADAM10 and ADAM17 or can be released from endothelial cells in response to IL-1β, IL-17, LPS, MIF, TNF, or PMA stimulation [147]. JAM-C is shown to promote adhesion of myeloid cells to the endothelium as well as facilitating myeloid cell retention and angiogenesis in RA [146,147].…”

“…JAM-C is also cleaved from the surface of endothelial cells by ADAM10 and ADAM17 or can be released from endothelial cells in response to IL-1β, IL-17, LPS, MIF, TNF, or PMA stimulation [147]. JAM-C is shown to promote adhesion of myeloid cells to the endothelium as well as facilitating myeloid cell retention and angiogenesis in RA [146,147]. In acute models of preclinical arthritis, treatment with anti-JAM-C antibody ameliorated antigen induced arthritis (AIA) by reducing synovial neutrophil migration and delayed the onset of K/BxN serum induced arthritis [148].…”