PMID- 33391544
OWN - NLM
STAT- MEDLINE
DCOM- 20210722
LR  - 20210722
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 11
IP  - 3
DP  - 2021
TI  - Tofacitinib restores the balance of gammadeltaTreg/gammadeltaT17 cells in rheumatoid arthritis by 
      inhibiting the NLRP3 inflammasome.
PG  - 1446-1457
LID - 10.7150/thno.47860 [doi]
AB  - 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 (gammadeltaTreg)/gammadeltaT17 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, gammadeltaTreg/gammadeltaT17 
      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 gammadeltaT17 cell activation in 
      RA. Results: TOF treatment decreased levels of gammadeltaT17 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 gammadeltaTreg/gammadeltaT17 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-1beta via downregulation of NLRP3. Furthermore, 
      experiments using Nlrp3(-/-) mice verified that the NLRP3 inflammasome mediated 
      the effect of TOF on gammadeltaT17 cell activation. Conclusions: Recovery of gammadeltaTreg/gammadeltaT17 
      cell balance was a novel mechanism by which TOF alleviated RA. Meanwhile, NLRP3 
      played a pivotal role in the process of TOF-mediated gammadeltaT17 cell activation.
CI  - (c) The author(s).
FAU - Yang, Xinyu
AU  - Yang X
AD  - Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou 
      Medical University, Wenzhou, China.
FAU - Zhan, Ning
AU  - Zhan N
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Jin, Yang
AU  - Jin Y
AD  - School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China.
FAU - Ling, Hanzhi
AU  - Ling H
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Xiao, Chipeng
AU  - Xiao C
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Xie, Zhen
AU  - Xie Z
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Zhong, Hao
AU  - Zhong H
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Yu, Xinxin
AU  - Yu X
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Tang, Runhua
AU  - Tang R
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Ma, Jinglan
AU  - Ma J
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Guan, Jubo
AU  - Guan J
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Yin, Guoyu
AU  - Yin G
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Wu, Gan
AU  - Wu G
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
FAU - Lu, Liangjing
AU  - Lu L
AD  - Department of Rheumatology, Shanghai Institute of Rheumatology, Renji Hospital, 
      Shanghai Jiao Tong University School of Medicine, Shanghai, China.
FAU - Wang, Jianguang
AU  - Wang J
AD  - Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical 
      University, Wenzhou, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210101
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
RN  - 0 (Cytokines)
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (NLRP3 protein, human)
RN  - 0 (Piperidines)
RN  - 0 (Pyrimidines)
RN  - 87LA6FU830 (tofacitinib)
SB  - IM
MH  - Animals
MH  - Arthritis, Experimental/*immunology
MH  - Arthritis, Rheumatoid/*immunology
MH  - Cytokines/immunology
MH  - Humans
MH  - Inflammasomes/*immunology
MH  - Intraepithelial Lymphocytes/*immunology
MH  - Macrophages/immunology
MH  - Male
MH  - Mice
MH  - Mice, Inbred DBA
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/*immunology
MH  - Piperidines/*immunology
MH  - Pyrimidines/*immunology
MH  - T-Lymphocytes, Regulatory/*immunology
PMC - PMC7738886
OTO - NOTNLM
OT  - Inflammation
OT  - NLRP3 inflammasome
OT  - Rheumatoid arthritis
OT  - Tofacitinib
OT  - gammadeltaT cells
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2021/01/05 06:00
MHDA- 2021/07/23 06:00
PMCR- 2021/01/01
CRDT- 2021/01/04 05:28
PHST- 2020/05/06 00:00 [received]
PHST- 2020/09/09 00:00 [accepted]
PHST- 2021/01/04 05:28 [entrez]
PHST- 2021/01/05 06:00 [pubmed]
PHST- 2021/07/23 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - thnov11p1446 [pii]
AID - 10.7150/thno.47860 [doi]
PST - epublish
SO  - Theranostics. 2021 Jan 1;11(3):1446-1457. doi: 10.7150/thno.47860. eCollection 
      2021.