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Theranostics 2021; 11(3):1446-1457. doi:10.7150/thno.47860 This issue Cite

Research Paper

Tofacitinib restores the balance of γδTreg/γδT17 cells in rheumatoid arthritis by inhibiting the NLRP3 inflammasome

Xinyu Yang^2#, Ning Zhan^1#, Yang Jin^3#, Hanzhi Ling¹, Chipeng Xiao¹, Zhen Xie¹, Hao Zhong¹, Xinxin Yu¹, Runhua Tang¹, Jinglan Ma¹, Jubo Guan¹, Guoyu Yin¹, Gan Wu¹, Liangjing Lu^4✉, Jianguang Wang^1✉

1. Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
2. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
3. School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China.
4. Department of Rheumatology, Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
#These authors contributed equally to this study.

✉ Corresponding authors: Jianguang Wang, Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University and Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325035, China. Tel: 86-577-86689978, E-mail: wz_wjgcom; Liangjing Lu, Department of Rheumatology, Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Tel: 86-18817821418, E-mail: lu_liangjingcom. More

Abstract

Objective: Tofacitinib (TOF) is a Janus kinase (JAK) inhibitor used in the treatment of rheumatoid arthritis (RA), but the mechanism of its action remains unclear. In this study, we investigated the influence of TOF on gamma delta regulatory T-cell (γδTreg)/γδT17 cell balance in RA and the role of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in this process.

Methods: We detected levels of inflammatory factors in the serum of RA patients before and after administration of TOF using an enzyme-linked immunosorbent assay (ELISA). A collagen-induced arthritis (CIA) model was constructed to investigate the effect of TOF on arthritis symptoms, γδTreg/γδT17 cell balance and the NLRP3 inflammasome. We used bone marrow-derived macrophages (BMDMs) to study the effect of TOF on NLRP3 inflammasome activation. Nlrp3^-/- mice were introduced to assess the influence of NLRP3 on γδT17 cell activation in RA.

Results: TOF treatment decreased levels of γδT17 cell-related cytokine interleukin-17 (IL-17) in RA patients. In addition, TOF intervention in the CIA model reduced joint inflammation and damage, rebalanced the γδTreg/γδT17 cell ratio and inhibited excessive NLRP3 inflammasome activation in draining lymph nodes and arthritic joints. BMDM intervention experiments demonstrated that TOF decreased the level of secreted IL-1β via downregulation of NLRP3. Furthermore, experiments using Nlrp3^-/- mice verified that the NLRP3 inflammasome mediated the effect of TOF on γδT17 cell activation.

Conclusions: Recovery of γδTreg/γδT17 cell balance was a novel mechanism by which TOF alleviated RA. Meanwhile, NLRP3 played a pivotal role in the process of TOF-mediated γδT17 cell activation.

Keywords: Rheumatoid arthritis, Tofacitinib, NLRP3 inflammasome, γδT cells, Inflammation

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