Local inhibition of TGF-\u03b21 signaling improves Th17/Treg balance but not joint pathology during experimental arthritis

Joyce Aarts,Joyce Aarts,Joyce Aarts,Elly L Vitters,Xinlai Chen,Xinlai Chen,Xinlai Chen,Monique M Helsen,Monique M Helsen,Monique M Helsen,Peter M Van Der Kraan,Arjan Van Caam,Fons A Van De Loo,Peter L Van Lent,Marije I Koenders,Marije I Koenders,Marije I Koenders,Renoud J Marijnissen,Renoud J Marijnissen,Renoud J Marijnissen,Birgitte Walgreen,Birgitte Walgreen,Birgitte Walgreen

doi:10.1038/s41598-022-07075-w

Abstract

TGF-β1 is an important growth factor to promote the differentiation of T helper 17 (Th17) and regulatory T cells (Treg). The potential of TGF-β1 as therapeutic target in T cell-mediated diseases like rheumatoid arthritis (RA) is unclear. We investigated the effect of TGF-β1 inhibition on murine Th17 differentiation in vitro, on human RA synovial explants ex vivo, and on the development of experimental arthritis in vivo. Murine splenocytes were differentiated into Th17 cells, and the effect of the TGF-βRI inhibitor SB-505124 was studied. Synovial biopsies were cultured in the presence or absence of SB-505124. Experimental arthritis was induced in C57Bl6 mice and treated daily with SB-505124. Flow cytometry analysis was performed to measure different T cell subsets. Histological sections were analysed to determine joint inflammation and destruction. SB-505124 potently reduced murine Th17 differentiation by decreasing Il17a and Rorc gene expression and IL-17 protein production. SB-505124 significantly suppressed IL-6 production by synovial explants. In vivo, SB-505124 reduced Th17 numbers, while increased numbers of Tregs were observed. Despite this skewed Th17/Treg balance, SB-505124 treatment did not result in suppression of joint inflammation and destruction. Blocking TGF-β1 signalling suppresses Th17 differentiation and improves the Th17/Treg balance. However, local SB-505124 treatment does not suppress experimental arthritis.

Highlights

TGF-β1 is an important growth factor to promote the differentiation of T helper 17 (Th17) and regulatory T cells (Treg)
We investigated the effect of inhibiting TGF-β1 signaling with the TGF-βRI inhibitor SB-505124 on murine Th17 differentiation in vitro, on cytokine production by human rheumatoid arthritis (RA) synovial explants ex vivo, and on the development of joint pathology in vivo during Th17-driven experimental arthritis
To investigate the effect of inhibition of TGF-β1 signaling on murine Th17 differentiation in vitro, murine splenocytes were cultured with different concentrations of TGF-β1 in the presence or absence of 5 μM SB-505124

Summary

Introduction

TGF-β1 is an important growth factor to promote the differentiation of T helper 17 (Th17) and regulatory T cells (Treg). We investigated the effect of TGF-β1 inhibition on murine Th17 differentiation in vitro, on human RA synovial explants ex vivo, and on the development of experimental arthritis in vivo. SB-505124 reduced Th17 numbers, while increased numbers of Tregs were observed Despite this skewed Th17/Treg balance, SB-505124 treatment did not result in suppression of joint inflammation and destruction. Abbreviations EAE Experimental autoimmune encephalitis H&E Hematoxylin and eosin PG Cartilage proteoglycan RA Rheumatoid arthritis RORc RAR-related orphan receptor C SCW Streptococcal cell wall Th17 T helper 17 cell T reg Regulatory T cell TGF-β Transforming growth factor beta. Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, that is characterized by chronic joint inflammation leading to destruction of articular cartilage and bone.

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