Leucine-rich alpha 2 glycoprotein promotes Th17 differentiation and collagen-induced arthritis in mice through enhancement of TGF-\u03b2-Smad2 signaling in na\xefve helper T cells

Hayato Urushima,Minoru Fujimoto,Takashi Mishima,Tomoharu Ohkawara,Tetsuji Naka,Hiromi Honda,Hyun Lee,Satoshi Serada,Hirohisa Kawahata

doi:10.1186/s13075-017-1349-2

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.

Highlights

Leucine-rich alpha 2 glycoprotein (LRG) has been identified as a serum protein elevated in patients with active rheumatoid arthritis (RA)
By a proteomic approach, we previously identified leucine-rich alpha 2 glycoprotein (LRG) as a serum protein that is elevated in patients with active rheumatoid arthritis (RA) [1]
Leucine-rich alpha glycoprotein (LRG) was intensively stained in the joints of WT mice with collagen-induced arthritis (CIA), but not in non-treated WT mice (Fig. 1b), indicating that LRG expression is upregulated in arthritic joints

Summary

Introduction

Leucine-rich alpha 2 glycoprotein (LRG) has been identified as a serum protein elevated in patients with active rheumatoid arthritis (RA). The function of LRG is ill-defined, LRG binds with transforming growth factor (TGF)-β and enhances Smad 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-Smad pathway that is pivotal for both Treg and Th17 differentiation. We previously identified leucine-rich alpha 2 glycoprotein (LRG) as a serum protein that is elevated in patients with active rheumatoid arthritis (RA) [1]. Other studies [3] and our own study [4] have shown that LRG binds with transforming growth factor (TGF)-β and/or its receptors and modulates downstream pathways of TGF-β signaling. The role of LRG in autoimmune arthritis is still unclear

Objectives

Methods

Results

Conclusion