Universität zu Köln

Yan, Shuaifeng, Golumba-Nagy, Viktoria, Kotschenreuther, Konstantin ORCID: 0000-0001-9455-2444, Thiele, Jan, Refaian, Nasrin ORCID: 0000-0001-8345-5972, Shuya, Deng, Gloyer, Lydia, Dittrich-Salamon, Mara, Meyer, Anja ORCID: 0000-0001-9904-5070, Heindl, Ludwig M. and Kofler, David M. (2022). Membrane-bound IL-6R is upregulated on Th17 cells and inhibits Treg cell migration by regulating post-translational modification of VASP in autoimmune arthritis. Cell. Mol. Life Sci., 79 (1). BASEL: SPRINGER BASEL AG. ISSN 1420-9071

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Yan, Shuaifeng UNSPECIFIED UNSPECIFIED UNSPECIFIED Golumba-Nagy, Viktoria UNSPECIFIED UNSPECIFIED UNSPECIFIED Kotschenreuther, Konstantin UNSPECIFIED orcid.org/0000-0001-9455-2444 UNSPECIFIED Thiele, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Refaian, Nasrin UNSPECIFIED orcid.org/0000-0001-8345-5972 UNSPECIFIED Shuya, Deng UNSPECIFIED UNSPECIFIED UNSPECIFIED Gloyer, Lydia UNSPECIFIED UNSPECIFIED UNSPECIFIED Dittrich-Salamon, Mara UNSPECIFIED UNSPECIFIED UNSPECIFIED Meyer, Anja UNSPECIFIED orcid.org/0000-0001-9904-5070 UNSPECIFIED Heindl, Ludwig M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kofler, David M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-663114
DOI:	10.1007/s00018-021-04076-2
Journal or Publication Title:	Cell. Mol. Life Sci.
Volume:	79
Number:	1
Date:	2022
Publisher:	SPRINGER BASEL AG
Place of Publication:	BASEL
ISSN:	1420-9071
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language T-CELLS; ACTIN CYTOSKELETON; INTEGRIN ADHESOME; PLASTICITY; CYTOKINES; DYNAMICS; ADHESION; DISTINCT; BALANCE; FAMILY Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66311