Tofacitinib Ameliorates Lupus Through Suppression of T Cell Activation Mediated by TGF-Beta Type I Receptor.

Qing Yan,Weiwei Chen,Lingyun Sun,Xianming Long,Hongwei Chen,Zhuoya Zhang,Hua Song,Xiaojun Tang,He Lin

doi:10.3389/fimmu.2021.675542

Abstract

Autoreactive T cells play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). TGF-β type I receptor (TGFβRI) is pivotal in determining T cell activation. Here, we showed that TGFβRI expression in naïve CD4+ T cells was decreased in SLE patients, especially in those with high disease activity. Moreover, IL-6 was found to downregulate TGFβRI expression through JAK/STAT3 pathway in SLE patients. In vitro, the JAK inhibitor tofacitinib inhibited SLE T cell activating by upregulating TGFβRI expression in a dose-dependent manner. In MRL/lpr mice, tofacitinib treatment ameliorated the clinical indicators and lupus nephritis, as evidenced by reduced plasma anti-dsDNA antibody levels, decreased proteinuria, and lower renal histopathological score. Consistently, tofacitinib enhanced TGFβRI expression and inhibited T cell activation in vivo. TGFβRI inhibitor SB431542 reversed the effects of tofacitinib on T cell activation. Thus, our results have indicated that tofacitinib can suppress T cell activation by upregulating TGFβRI expression, which provides a possible molecular mechanism underlying clinical efficacy of tofacitinib in treating SLE patients.

Highlights

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease and characterized by excessive activation of T and B cells, as well as the production of various autoantibodies, which affects many organs, especially the kidneys [1, 2]
We found that TGFbRI expression exhibited an inverse correlation with disease activity in systemic lupus erythematosus (SLE) patients and that IL-6 triggered Janus kinase family (JAKs)/STAT3 pathway was involved in the downregulation of TGFbRI
Based on the SLE disease activity index (SLEDAI) score, SLE patients were divided into two subgroups (0-10, stable and mild disease activity; >10, moderate to severe disease activity)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease and characterized by excessive activation of T and B cells, as well as the production of various autoantibodies, which affects many organs, especially the kidneys [1, 2]. Cyclosporine A and tacrolimus have good therapeutic effects by suppressing T cell activation in lupus patients. Their obvious side effects such as nephrotoxicity limit the clinical use [5]. Many biological agents that aim to control T cell activation with fewer side effects have been developed for clinical trials, but some of Tofacitinib Ameliorates Lupus by TGFbRI them have failed in the end [5, 6]. There is an urgent need to identify potential targets and develop novel therapeutic strategies against SLE [7]

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Conclusion