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Membrane-bound IL-6R is upregulated on Th17 cells and inhibits Treg cell migration by regulating post-translational modification of VASP in autoimmune arthritis
PMU Author
L. M. Heindl
All Authors
S. Yan, V. Golumba-Nagy, K. Kotschenreuther, J. Thiele, N. Refaian, D. Shuya, L. Gloyer, M. Dittrich-Salamon, A. Meyer, L. M. Heindl, D. M. Kofler
Journal association
CELLULAR AND MOLECULAR LIFE SCIENCES
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.
Keywords
Animals Arthritis, Experimental/chemically induced/metabolism/pathology Arthritis, Rheumatoid/metabolism/*pathology CD8-Positive T-Lymphocytes/cytology/immunology/metabolism Cell Adhesion Molecules/*metabolism Cell Movement Humans Interleukin-6/blood Mice Mice, Inbred DBA Microfilament Proteins/*metabolism Phosphoproteins/*metabolism Phosphorylation Receptors, Interleukin-6/*metabolism T-Lymphocytes, Regulatory/cytology/*metabolism Th17 Cells/cytology/*metabolism Up-Regulation Vasodilator-Stimulated Phosphoprotein Autoimmune arthritis Collagen-induced arthritis Il-6 Regulatory T cells T cell migration Vasp