Abstract
Regulatory T-cell (Treg)/T-helper 17 (Th17) cell balance plays an important role in the progression of rheumatoid arthritis (RA). Our study explored the protective effect of protectin DX (PDX), which restored Treg/Th17 cell balance in RA, and the role of the nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome pathway in this process. Using mass spectrometry, we discovered that level of PDX decreased in active-RA patients and increased in inactive-RA patients compared with HCs, and serum PDX was a potential biomarker in RA activity detection (area under the curve [AUC] = 0.86). In addition, a collagen-induced arthritis (CIA) mice model was constructed and PDX obviously delayed RA progression in the CIA model, upregulating Tregs and anti-inflammatory cytokines while downregulating Th17 cells and pro-inflammatory cytokines. Moreover, NLRP3 knockout and rescue experiments demonstrated that NLRP3 participated in PDX-mediated Treg/Th17 cell balance restoration, joint injury amelioration and inflammatory-response attenuation using Nlrp3−/− mice. Furthermore, microarray and verified experiments confirmed that PDX reduced NLRP3 expression via miRNA-20a (miR-20a). In summary, we confirmed for the first time that PDX could effectively ameliorate CIA progression by restoring Treg/Th17 cell balance, which was mediated by inhibition of the NLRP3 inflammasome pathway via miR-20a.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease that progressively destroys the articular cartilage and bones of the joints[1]
It is reported that Treg/T-helper 17 (Th17) cell balance might be regulated via the signal transducer and activator of transcription (STAT)/nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) axis or by nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling in a collagen-induced arthritis (CIA) model[7,8]
We are the first to report a decrease in Protectin DX (PDX) in patients with active RA and an increase in PDX in those with inactive RA compared with HCs, and that serum PDX levels correlated negatively with DAS28
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease that progressively destroys the articular cartilage and bones of the joints[1]. Its precise pathogenesis remains unclear, studies indicate that regulatory T-cell (Treg)/T-helper 17 (Th17) cell imbalance might play a role in the progression of RA2. Th17 cells mediate the pro-inflammatory response via interleukin17A (IL-17A) and tumor necrosis factor alpha (TNF-α). It is reported that Treg/Th17 cell balance might be regulated via the signal transducer and activator of transcription (STAT)/nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) axis or by nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling in a collagen-induced arthritis (CIA) model[7,8]. Jin et al Cell Death and Disease (2021)12:280 investigation into the mechanism of Treg/Th17 cell balance regulation seemed valuable to discovering the potential pathogenesis and therapeutic target of RA. Our previous study indicated that two other SPMs, maresin 1 (MaR1) and resolvin D1 (RvD1), moderated the inflammatory response in RA10,11
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