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S100A4 regulates the Src-tyrosine kinase dependent differentiation of Th17 cells in rheumatoid arthritis

Journal article
Authors Mikael Brisslert
Li Bian
Mattias Svensson
R. F. Santos
Ing-Marie Jonsson
I. Barsukov
Malin Erlandsson
Karin Andersson
A. M. Carmo
Maria Bokarewa
Published in Biochimica Et Biophysica Acta-Molecular Basis of Disease
Volume 1842
Issue 11
Pages 2049-2059
ISSN 0925-4439
Publication year 2014
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Pages 2049-2059
Language en
Links dx.doi.org/10.1016/j.bbadis.2014.07...
Keywords S100A4, Th17 cell, TCR, Src-tyrosine kinase, Arthritis, CD5, ROR-GAMMA-T, HUMAN ARTICULAR CHONDROCYTES, NONMUSCLE MYOSIN-IIA, GROWTH-FACTOR-BETA, METASTASIN S100A4, PROTEIN S100A4, EFFECTOR, FUNCTION, DENDRITIC CELLS, UP-REGULATION, FYN KINASE, Biochemistry & Molecular Biology, Biophysics, Cell Biology
Subject categories Biochemistry and Molecular Biology

Abstract

Objectives: To evaluate the role of S100A4, a calcium-binding regulator of nonmuscle myosin assembly, for T-cell responses in rheumatoid arthritis. Methods: Arthritis was induced in the methylated bovine serum albumin (mBSA)-immunized mice lacking the entire S100A4 protein (S100A4KO) and in wild-type counterparts treated with short hairpin ribonucleic acid (shRNA)-lentiviral constructs targeting S100A4 (S100A4-shRNA). The severity of arthritis was evaluated morphologically. T-cell subsets were characterized by the expression of master transcription factors, and functionally by proliferation activity and cytokine production. The activity of the Scr-kinases Fyn and Lck was assessed by the autophosphorylation of C-terminal thyrosine and by the phosphorylation of the CD5 cytodomain. The interaction between S100A4 and the CD5 cytodomain was analysed by nuclear magnetic resonance spectrophotometry. Results: S100A4-deficient mice (S100A4KO and S100A4-shRNA) had significantly alleviated morphological signs of arthritis and joint damage. Leukocyte infiltrates in the arthritic joints of S100A4-deficient mice accumulated Foxp3(+) Treg cells, while the number of ROR gamma t(+) and (pTyr705)STAT3(+) cells was reduced. S100A4-deficient mice had a limited formation of Th17-cells with low retinoic acid orphan receptor gamma t (ROR gamma t) mRNA and IL17 production in T-cell cultures. S100A4-deficient mice had a low expression and activity of T-cell receptor (TCR) inhibitor CD5 and low (pTyr705)STAT3 (signal transducer and activator of transcription 3), which led to increased (pTyr352)ZAP-70 (theta-chain associated protein kinase of 70 kDa), lymphocyte proliferation and production of IL2. In vitro experiments showed that S100A4 directly binds Lck and Fyn and reciprocally regulates their kinase activity towards the CD5 cytodomain. Spectrometry demonstrates an interaction between the CD5 cytodomain and EF2-binding sites of S100A4. Conclusion: The present. study demonstrates that S100A4 plays an important part in the pathogenesis of arthritis. It controls CD5-dependent differentiation of Th17 cells by regulating the activity of the Src-family kinases Lck and Fyn. (C) 2014 Elsevier B.V. All rights reserved.

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