Membrane-bound IL-6R is upregulated on Th17 cells and inhibits Treg cell migration by regulating post-translational modification of VASP in autoimmune arthritis

Shuaifeng Yan,David M Kofler,Jan Thiele,Lydia Gloyer,Viktoria Golumba-Nagy,Anja Meyer,Nasrin Refaian,Deng Shuya,Mara Dittrich-Salamon,Ludwig M Heindl,Konstantin Kotschenreuther

doi:10.1007/s00018-021-04076-2

Shuaifeng Yan, David M Kofler + Show 9 more

Open Access

https://doi.org/10.1007/s00018-021-04076-2

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Abstract

Autoimmune arthritis is characterized by impaired regulatory T (Treg) cell migration into inflamed joint tissue and by dysregulation of the balance between Treg cells and Th17 cells. Interleukin-6 (IL-6) is known to contribute to this dysregulation, but the molecular mechanisms behind impaired Treg cell migration remain largely unknown. In this study, we assessed dynamic changes in membrane-bound IL-6 receptor (IL6R) expression levels on Th17 cells by flow cytometry during the development of collagen-induced arthritis (CIA). In a next step, bioinformatics analysis based on proteomics was performed to evaluate potential pathways affected by altered IL-6R signaling in autoimmune arthritis. Our analysis shows that membrane-bound IL-6R is upregulated on Th17 cells and is inversely correlated with IL-6 serum levels in experimental autoimmune arthritis. Moreover, IL-6R expression is significantly increased on Th17 cells from untreated patients with rheumatoid arthritis (RA). Interestingly, CD4+ T cells from CIA mice and RA patients show reduced phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Bioinformatics analysis based on proteomics of CD4+ T cells with low or high phosphorylation levels of VASP revealed that integrin signaling and related pathways are significantly enriched in cells with low phosphorylation of VASP. Specific inhibition of p-VASP reduces the migratory function of Treg cells but has no influence on effector CD4+ T cells. Importantly, IL-6R blockade restores the phosphorylation level of VASP, thereby improving the migratory function of Treg cells from RA patients. Thus, our results establish a link between IL6R signaling and phosphorylation of VASP, which controls Treg cell migration in autoimmune arthritis.

Highlights

Rheumatoid arthritis (RA) is one of the most prevalent autoimmunity diseases and is characterized by chronic inflammation, bone destruction and extra-articular manifestations [1,2,3,4]
We investigated dynamic characteristics in membrane-bound IL-6 receptor expression on Th17 cells in the collagen-induced arthritis (CIA) mouse model of autoimmune arthritis
Immunohistochemistry staining of inflamed joints shows that Th17 cells migrate into the synovial tissue of CIA joints whereas no Th17 cells are found in the joint of control mice (Fig. 1d)

Summary

Introduction

Rheumatoid arthritis (RA) is one of the most prevalent autoimmunity diseases and is characterized by chronic inflammation, bone destruction and extra-articular manifestations [1,2,3,4]. The frequency of Th17 cells and the level of IL-17 are increased in the peripheral blood and in the synovial tissue of RA patients as compared to healthy control. Some researchers report a higher level of Treg cells in the synovial fluid [13, 14]. This contradictory results may be explained by different strategies used to identify Treg cells and by inhomogeneity of patient populations. It has been shown that the suppressive capacity of Treg cells gets inhibited in the synovial fluid of RA patients while Treg cells in peripheral blood remain suppressive [15]. Due to the complexity and interactions between Treg and Th17 subsets, the underlying molecular mechanism regulating their interaction needs to be investigated to better understand their role in RA pathogenesis

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