Selective blockade of IL-21 by myricetin impedes T follicular helper cell differentiation by negatively regulating the JAK/STAT/Bcl-6 pathway in a rheumatoid arthritis animal model.

Interleukin (IL)-21 is a major lineage-defining factor that promotes Tfh cell differentiation. The current study investigated the molecular basis of myricetin, a flavonoid that impedes IL-21-mediated differentiation of Tfh cells in RA. Through high-throughput virtual screening of natural compounds that inhibit IL-21, we found that myricetin binds to IL-21 and hampers its interaction with IL-21 receptor (IL-21R). Our in vivo studies demonstrated that myricetin treatment ameliorated the clinical manifestations in adjuvant-induced arthritis (AIA) mice by reducing paw thickness and cellular infiltration. In addition, myricetin inhibited splenic Tfh cell differentiation and IL-21 production in AIA mice. Myricetin negatively regulates JAK/STAT signaling and the downstream Bcl-6 transcription factor at the molecular level, which arrests Tfh cell differentiation. Our current research proposal to target IL-21 with myricetin inevitably represents a new molecular approach that expedites new alternative drugs for rheumatoid arthritis therapy. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03880-w.

Myricetin ameliorates the IL-21-induced tumorigenic phenotype of adjuvant-induced arthritis FLS by modulating the choline kinase signaling cascade.

The synovial intimal lining is mainly governed by fibroblast-like synoviocytes (FLS), which portray a transformed tumor-like phenotype in rheumatoid arthritis (RA). Among the diverse cytokines that engender FLS, interleukin-21 (IL-21) was reported to stimulate hyperproliferation and perpetuate inflammation. Recently, choline kinase (ChoKα) has been reported to be an essential enzyme aiding RA-FLS hyperproliferation by altering phosphatidylcholine biosynthesis. The current study aimed to elucidate the therapeutic efficacy of myricetin, a flavonoid, in abating the IL-21-induced tumor-like phenotype of adjuvant-induced arthritis (AIA)-FLS via the ChoKα signaling cascade. Our results showed that myricetin suppressed IL-21 receptor expression and activation of the ChoKα signaling cascade (N-Ras, Ral-GDS, and PI3K) in IL-21-induced AIA-FLS. Consequently, myricetin treatment decreased ChoKα and PLD2 enzymatic activity and inhibited the proliferative, migratory, and invasive properties of AIA-FLSs. Our results demonstrated that myricetin could be a promising anti-arthritic compound by abating IL-21-induced hyperproliferation, migration, and invasive behavior of AIA-FLS by downregulating the ChoKα signaling cascade.