Angiogenesis in Rheumatoid Arthritis Is Fostered Directly by Toll-like Receptor 5 Ligation and Indirectly Through Interleukin-17 Induction
Article first published online: 26 JUL 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 8, pages 2024–2036, August 2013
How to Cite
Kim, S.-j., Chen, Z., Chamberlain, N. D., Volin, M. V., Swedler, W., Volkov, S., Sweiss, N. and Shahrara, S. (2013), Angiogenesis in Rheumatoid Arthritis Is Fostered Directly by Toll-like Receptor 5 Ligation and Indirectly Through Interleukin-17 Induction. Arthritis & Rheumatism, 65: 2024–2036. doi: 10.1002/art.37992
- Issue published online: 26 JUL 2013
- Article first published online: 26 JUL 2013
- Accepted manuscript online: 10 MAY 2013 01:58PM EST
- Manuscript Accepted: 23 APR 2013
- Manuscript Received: 3 DEC 2012
- NIH. Grant Number: AR-055240
- Rheumatology Research Foundation (Within Our Reach Program grant)
- US Department of Defense. Grant Number: Award PR-093477
- Arthritis Foundation (Innovative Research grant)
To examine the impact of Toll-like receptor 5 (TLR-5) on endothelial cell function in rheumatoid arthritis (RA) and vascularization in collagen-induced arthritis (CIA).
Endothelial cell migration and tube formation assays were used to demonstrate the direct role of TLR-5 ligation in angiogenesis. Mice with CIA were treated with the TLR-5 agonist flagellin to document the effect of TLR-5 ligation in RA pathology. Vascularization in CIA was determined by immunohistochemical analysis and determination of cytokine levels in ankle joints. Spleen Th17 cells and joint interleukin-17 (IL-17) were quantified by fluorescence-activated cell sorting analysis and enzyme-linked immunosorbent assay. The development of Th17 cells induced by TLR-5 ligation was validated in RA peripheral blood mononuclear cells.
Ligation of TLR-5 to endogenous ligands expressed in RA synovial fluid contributed to endothelial cell infiltration and tube formation. Furthermore, treatment with flagellin after the onset of CIA exacerbated joint inflammation; in contrast, inflammation in control mice remained at a plateau phase. We showed that TLR-5–enhanced disease severity was attributable to Th17 cell differentiation and joint vascularization in CIA. Examination of the underlying mechanism using RA peripheral blood mononuclear cells documented that ligation of TLR-5 in myeloid cells and production of Th17–promoting cytokines were necessary for Th17 cell polarization. Additionally, we demonstrated that blockade of the IL-17 cascade markedly reduced endothelial cell migration activated by flagellin-conditioned medium, suggesting that TLR-5 ligation can mediate RA angiogenesis either directly by attracting endothelial cells or indirectly by fostering Th17 cell development.
Our data demonstrate a novel role for TLR-5 in RA angiogenesis; thus, TLR-5 may be a promising new target for RA treatment.