Protectin DX restores Treg/Th17 cell balance in rheumatoid arthritis by inhibiting NLRP3 inflammasome via miR-20a

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.

Yanghe Decoction Suppresses the Experimental Autoimmune Thyroiditis in Rats by Improving NLRP3 Inflammasome and Immune Dysregulation

“…These data suggested that NLRP3 inflammasome might participate in the regulation of Treg/Th17 cell balance in autoimmune diseases. In a recent study, Jin et al confirmed that protect in DX (PDX) could restore Treg/Th17 cell balance in RA by inhibiting NLRP3 inflammasome via miR-20a ( Jin et al, 2021 ). Considering that the NLRP3 inflammasome plays an important role in the Treg/Th17 cell balance, which in turn regulates autoimmunity, we speculated that YH treatment alleviated autoimmune thyroiditis in rats, which could be due to the Th17/Treg rebalancing regulated by Wnt/β-catenin pathway through NLRP3 inflammasome deactivation ( Figure 11 ).…”

Dysfunctions, Molecular Mechanisms, and Therapeutic Strategies of Regulatory T Cells in Rheumatoid Arthritis

“…The balance between Tregs and Th17 is the key point in the maintenance of immune homeostasis. Similarities to that of other ADs, such as systemic lupus erythematosus and autoimmune hepatitis, the pathogenesis of RA has been observed to involve an imbalance between Tregs and Th17 (Jin et al, 2021). The inflammatory cytokine environment is a key driver that could globally push Tregs/Th17 toward imbalance because the combination of TGF-β and IL-6 allows T-cell differentiation toward the Th17 phenotype, whereas if TGF-β is present alone, T cells will differentiate or revert into iTregs in vitro (Bettelli et al, 2006).…”

Regulation of T-Cell Immune Responses by Pro-Resolving Lipid Mediators

“…Of interest, in the last years, lipidomic analysis of plasma or serum recovered from patients with chronic inflammatory disorders implicating pathogenic T-cell responses constantly showed decreased SPM concentrations at the time of active disease, compared with healthy and/or inactive disease status. This was reported for MaR1 and PD1 in rheumatoid arthritis (RA) (59,85) and for RvD1 in SLE, MS, and chronic heart failure (63,83,84). Lower levels of RvD3, RvD4, and RvE3 were also observed in a small cohort of stage III RA patients, with concomitant increase in inflammatory TBX2 (86).…”