A glimpse on the role of IL-21 in psoriatic arthritis pathogenesis.

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy affecting the skin, entheses, and joints. Over the past decade, experimental evidence has revealed the activation of several immune cells and signaling cascades in modulating the pathophysiology of PsA. Recently, targeted therapies have been developed to combat the severity of disease. However, with diverse etiologies, flareups, and relapses, there has been an increased prevalence and mortality associated with PsA in recent years. Therefore, it is imperative to investigate new potential mediators and combination therapies to manage PsA pathogenesis. IL-21, an immunomodulatory cytokine, has pleiotropic effects on immune cells and the protein cascades involved in PsA pathogenesis. Recently, emerging evidence of increased IL-21 levels in patients with PsA has engendered much enthusiasm for its potential as a therapeutic target. Here, we unmasked IL-21 as a significant modulator of PsA pathogenesis and reviewed the comorbidities associated with the disease, further cataloging future therapeutic modalities to ameliorate PsA progression.

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.