Open AccessAngiogenesis in Rheumatoid Arthritis Is Fostered Directly by Toll‐like Receptor 5 Ligation and Indirectly Through Interleukin‐17 Induction
Author(s) -
Kim Seungjae,
Chen Zhenlong,
Chamberlain Nathan D.,
Volin Michael V.,
Swedler William,
Volkov Suncica,
Sweiss Nadera,
Shahrara Shiva
Publication year - 2013
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.37992
Subject(s) - angiogenesis , immunology , inflammation , medicine , arthritis , interleukin 17 , cytokine , cancer research
Objective 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). Methods 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. Results 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. Conclusion Our data demonstrate a novel role for TLR‐5 in RA angiogenesis; thus, TLR‐5 may be a promising new target for RA treatment.