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

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. Nlrp 3 -/- 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.

Exosome-inflammasome crosstalk and their roles in inflammatory responses

“…The common PRRs in the canonical inflammasome pathway include NLRP1 4 , NLRP3 33 , 34 , NLR family apoptosis inhibitory protein (NAIP)-NLRC4 35 , 36 , pyrin 37 , 38 , and AIM2 28 , 39 . These PRRs recognize different PAMPs and DAMPs.…”

Inflammasome and Its Therapeutic Targeting in Rheumatoid Arthritis

“…A recent study showed that IL-6 could induce activation of the NLRP3 inflammasome via the cathepsin B (CTSB)/S100A9-mediated pathway and promote joint inflammation in CIA mice, suggesting that the IL-6/NLRP3 pathway may also be a novel target for RA therapy ( 110 ). In addition, tofacitinib restores the cellular balance of γδ-Treg/γδ-T17 cells in the CIA model, and a balanced γδ-Treg/γδ-T17 cell ratio inhibits NLRP3 expression and reduces IL-1β secretion ( 111 ). Recent studies have shown increased expression of long noncoding RNA myocardial infarction-associated transcript (lncRNA MIAT) in the myocardial tissue and synovium of CIA mice.…”

NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases

“…firstly found that protectin DX downregulates Th17 cells and pro-inflammatory cytokines and upregulates Tregs and anti-inflammatory cytokines by inhibiting NLRP3 inflammasome activation via miR-20a ( 89 ). Tofacitinib effectively ameliorates the severity of RA by restoring Treg/Th17 cell balance via reducing NLRP3 inflammasome activation in arthritic joints and draining lymph nodes ( 87 ). NLRP3 inflammasome can also mediate secretion of Fas-associated death domain, which is a pivotal adaptor molecule in innate immunity and inflammation ( 151 ).…”