RA is a chronic inflammatory autoimmune disorder that starts in the young to middle adult years and may lead to complete joint destruction. There is no cure for RA at present and a substantial percentage of patients do no respond to current therapy, therefore novel therapeutic approaches are urgently needed. Angiogenesis is an early and a critical event that fosters RA chronic inflammation and bone erosion by facilitating unbalanced leukocyte migration and pannus formation. Hence inhibition of angiogenesis may lead to identifying novel therapeutic approaches for RA. Macrophages are hypoxia sensors that initiate and maintain angiogenesis in RA synovium. We found that CCR7 was the most highly upregulated gene in macrophages obtained from RA synovial fluid compared to the normal myeloid cells. Consistently macrophages in the RA synovial tissue lining and endothelial cells in the sublining express elevated levels of CCR7 and its ligand CCL21. We uncovered that synovial CCL21 but not CCL19 is a novel and potent chemoattractant for CCR7+ endothelial cells, which plays a pivotal role in RA tube and blood vessel formation. In RA synovial tissue explants, CCL21 driven angiogenesis can be also induced indirectly through VEGF production. We found that the endothelial CCL21 and CCR7 expression is modulated by IL-17 cascade. We further document that that CCL21 is the missing link between IL-17 and VEGF mediated vascularization as CCL21 blockade markedly suppresses IL-17 induced VEGF expression. Based on our supportive data, we hypothesize that angiogenesis is directly promoted by CCL21 ligation to endothelial CCR7 and indirectly induced through VEGF production from RA synovial tissue fibroblasts. We also postulate that CCL21 links the IL-17 and VEGF angiogenesis process, therefore blockade of CCL21/CCR7 cascade will disrupt the IL-17 and VEGF interconnection, thus resolving RA neovascularization. Hence novel translational studies are proposed to provide an in depth understanding of how CCL21/CCR7 cascade is connected to IL-17 mediated arthritis and vascularization. Moreover we will examine the underlying mechanism by which ligation of CCL21 to CCR7 contributes to RA angiogenesis and whether disruption of CCL21 binding to CCR7 can be used as a promising new therapeutic target in RA through disconnecting the link between IL-17 and VEGF mediated neovascularization.
We have characterized novel genes that are greatly upregulated in rheumatoid arthritis (RA) compared to normal joint tissues and blood cells. Further we have strong evidence how these genes may effect RA disease progression. In this proposal our aim is to identify the inflammatory factors that modulate these genes of interest, determine the mechanism by which these genes contribute to disease pathogenesis and lastly to investigate whether they can be employed as an effective target for RA treatment. Successful completion of this proposal will provide transformative insights into RA pathology that will lead t identifying novel therapeutic targets.
|Kim, Seung-Jae; Chen, Zhenlong; Chamberlain, Nathan D et al. (2014) Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis. J Immunol 193:3902-13|