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Leucine-rich alpha 2 glycoprotein promotes Th17 differentiation and collagen-induced arthritis in mice through enhancement of TGF-β-Smad2 signaling in naïve helper T cells

Authors
  • Urushima, Hayato1
  • Fujimoto, Minoru1, 2
  • Mishima, Takashi1
  • Ohkawara, Tomoharu1
  • Honda, Hiromi1
  • Lee, Hyun1
  • Kawahata, Hirohisa3
  • Serada, Satoshi1, 2
  • Naka, Tetsuji1, 2
  • 1 Laboratory of Immune Signal, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan , Ibaraki (Japan)
  • 2 Kochi University, Center for Intractable Immune Disease, Kochi Medical School, Kochi, Japan , Kochi (Japan)
  • 3 Morinomiya University of medical science, Department of Medical Technology, Osaka, Japan , Osaka (Japan)
Type
Published Article
Journal
Arthritis Research & Therapy
Publisher
Springer Science and Business Media LLC
Publication Date
Jun 14, 2017
Volume
19
Issue
1
Identifiers
DOI: 10.1186/s13075-017-1349-2
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundLeucine-rich alpha 2 glycoprotein (LRG) has been identified as a serum protein elevated in patients with active rheumatoid arthritis (RA). Although the function of LRG is ill-defined, LRG binds with transforming growth factor (TGF)-β and enhances Smad2 phosphorylation. Considering that the imbalance between T helper 17 (Th17) cells and regulatory T cells (Treg) plays important roles in the pathogenesis of RA, LRG may affect arthritic pathology by enhancing the TGF-β-Smad2 pathway that is pivotal for both Treg and Th17 differentiation. The purpose of this study was to explore the contribution of LRG to the pathogenesis of arthritis, with a focus on the role of LRG in T cell differentiation.MethodsThe differentiation of CD4 T cells and the development of collagen-induced arthritis (CIA) were examined in wild-type mice and LRG knockout (KO) mice. To examine the influence of LRG on T cell differentiation, naïve CD4 T cells were isolated from LRG KO mice and cultured under Treg- or Th17-polarization condition in the absence or presence of recombinant LRG.ResultsIn the CIA model, LRG deficiency led to ameliorated arthritis and reduced Th17 differentiation with no influence on Treg differentiation. By addition of recombinant LRG, the expression of IL-6 receptor (IL-6R) was enhanced through TGF-β-Smad2 signaling. In LRG KO mice, the IL-6R expression and IL-6-STAT3 signaling was attenuated in naïve CD4 T cells, compared to wild-type mice.ConclusionsOur findings suggest that LRG upregulates IL-6R expression in naïve CD4 T cells by the enhancement of TGF-β-smad2 pathway and promote Th17 differentiation and arthritis development.

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