期刊
THERANOSTICS
卷 11, 期 3, 页码 1446-1457出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.47860
关键词
Rheumatoid arthritis; Tofacitinib; NLRP3 inflammasome; gamma delta T cells; Inflammation
资金
- Public Technology Applied Research Foundation of Zhejiang Province [LGF18H060009]
- National Natural Science Foundations of China [81971539, 81672129]
- Key Research and Development Program of Zhejiang Province [2019C03023, 2019C03011]
- National and Zhejiang College Students Innovative Entrepreneurial Training Program of China [201810343040X, 2019R413057]
Tofacitinib (TOF) restores the balance of gamma delta regulatory T-cells/gamma delta T17 cells in rheumatoid arthritis (RA) patients by reducing levels of gamma delta T17 cell-related cytokine and inhibiting excessive NLRP3 inflammasome activation.
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 (gamma delta Treg)/gamma delta T17 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, gamma delta Treg/gamma delta T17 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.dT17 cell activation in RA. Results: TOF treatment decreased levels of gamma delta T17 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 gamma delta Treg/gamma delta T17 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-1 beta via downregulation of NLRP3. Furthermore, experiments using Nlrp3(-/-) mice verified that the NLRP3 inflammasome mediated the effect of TOF on gamma delta T17 cell activation. Conclusions: Recovery of gamma delta Treg/gamma delta T17 cell balance was a novel mechanism by which TOF alleviated RA. Meanwhile, NLRP3 played a pivotal role in the process of TOF-mediated gamma delta T17 cell activation.
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