Fisetin inhibits pristine-induced systemic lupus erythematosus in a murine model through CXCLs regulation

Abstract

Systemic lupus erythematosus (SLE) is associated with an increased risk of vascular complications. Lupus nephritis is a major manifestation of SLE in the clinic. Lupus nephritis is elevated by T helper type 17 (Th17) cells, the major pro-inflammatory T-cell subset, leading to autoimmunity modulation. Therapeutic treatments targeting leukocyte recruitment may be useful in attenuating vascular complications linked to SLE progression. 3,7,3',4'-Tetrahydroxyflavone (fisetin) is a flavonol and a member of the flavonoid polyphenols. It is present in various fruits and vegetables, including persimmons, apples, kiwis, grapes, onions, strawberries and cucumbers. In the present study, the effects of fisetin against SLE induced by pristane (PRI) were evaluated in mice. Fisetin was indicated to reduce PRI-induced anti-double stranded DNA, anti- small nuclear ribonucleoprotein and the ratio of albumin to creatinine in urine. In addition, the chemokine (C-X-C motif) ligand (CXCL) signaling pathway was activated for PRI treatment, which was reversed by fisetin administration by reducing CXCL-1 and 2, chemokine (C-C motif) ligand 3, as well as CXC receptor 2 expression. In addition, the induction of inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-α, IL-1β, as well as the chemokine interferon-γ, by PRI were downregulated by fisetin treatment in mice. Furthermore, Th17 cells and their associated cytokines were highly induced by PRI treatment, which was inhibited by fisetin administration. The present results indicated that fisetin may be an effective management for SLE by targeting the CXCL signaling pathway and regulating Th17 differentiation during lupus nephritis development.

Naringenin mitigates autoimmune features in lupus-prone mice by modulation of T-cell subsets and cytokines profile

“…Furthermore, the oral administration of Naringenin avoided the development of collagen fibers compared with vehicle. It seems that Naringenin has the ability to protect against kidney injury, this effect has also been described previously for other flavonoids administered in lupus-prone mice models [35,36,52].…”

“…Proteinuria reflect the grade of lupus nephritis and constitutes one biomarker for disease monitoring [41]. Although it has been reported that the administration of flavonoids such as Baicalin or isoflavones for a short period reduces proteinuria [35,53], the long-term effect of Naringenin or other flavonoids in the urine protein level has been poorly evaluated [52]. Here, we demonstrated that the highest dose Naringenin decreased the proteinuria score from the first to the third month of treatment.…”

“…In this study, compared to treatment periods previously reported for other flavonoids [34,35,52], we evaluated the long-term effect (seven months of treatment) of oral administration of Naringenin on the development of autoimmunity in B6.MRL-Fas lpr /J lupus-prone mice. B6.MRL-Fas lpr /J mice resembles SLE in humans with production of several autoantibodies, imbalance in serum concentration of cytokines and abnormalities in lymphocytes subsets.…”

“…In B6.MRL-Fas lpr /J mice splenomegaly is a classic feature of SLE and is closely related to an accelerated lymphoproliferation. Previous reports have shown that oral supplementation of Astilbin (20, 40 mg/kg in MRL/MpJ-Fas lpr /J mice) or Fisetin (25,50 or 100 mg/kg in pristineinduced SLE) and intraperitoneal injection of Baicalin (200 mg/kg MRL/MpJ-Fas lpr /J mice) prevent the enlargement of the spleen [34,35,52]. Our results demonstrated that both doses of Naringenin ameliorated the development of splenomegaly through the reduction in accumulation of lymphocytes, which might be explained by the inhibition or reduction of proliferation, an effect previously reported for Naringenin on in vitro assays without affect the cell viability [31,32].…”

A benzimidazole inhibitor attenuates sterile inflammation induced in a model of systemic autoinflammation in female mice

“…In order to induce inflammation in mice, the animals were intraperitoneally (i.p.) injected with 0.5 ml of pristane (2,6,10,14-tetramethylpentadecane (TMPD)) (Sigma, St. Louis, MO) as previously described 21 – 24 . PBS was administered to the control group.…”