title: Angiogenesis in rheumatoid arthritis is fostered directly by toll-like receptor 5 ligation and indirectly through interleukin-17 induction.
abstract: 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.
  
  
  CONCLUSIONS
  Our data demonstrate a novel role for TLR-5 in RA angiogenesis; thus, TLR-5 may be a promising new target for RA treatment.
authors.affiliation: University of Illinois at Chicago, IL60612, USA.
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Kim
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Chen
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Chamberlain
authors.forename: Michael V
authors.initials: MV
authors.lastname: Volin
authors.forename: William
authors.initials: W
authors.lastname: Swedler
authors.forename: Suncica
authors.initials: S
authors.lastname: Volkov
authors.forename: Nadera
authors.initials: N
authors.lastname: Sweiss
authors.forename: Shiva
authors.initials: S
authors.lastname: Shahrara
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005408:Flagellin / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D007596:Joints / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013582:Synovial Fluid / Q000187:drug effects / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000473:pathology; D051198:Toll-Like Receptor 5 / Q000819:agonists*
chemical_list: D016207:Cytokines; D020381:Interleukin-17; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin