Hesperidin inhibits synovial cell inflammation and macrophage polarization through suppression of the PI3K/AKT pathway in complete Freund's adjuvant-induced arthritis in mice
Hesperidin inhibits synovial cell inflammation and macrophage polarization through suppression of the PI3K/AKT pathway in complete Freund's adjuvant-induced arthritis in mice
复制标题
DOI：
10.1016/j.cbi.2019.04.002
复制
发表时间：
2019-06-01
影响因子：
5.1
通讯作者：
Cai, Daozhang
中科院分区：
文献类型：
--
作者：
Qi, Weizhong;Lin, Chuangxin;Cai, Daozhang
类风湿性关节炎（RA）是一种以滑膜炎为特征的自身免疫性疾病。滑膜炎可通过释放炎症因子和金属蛋白酶（MMP）引起关节损伤。因此，有必要寻找能够控制RA过程中滑膜炎的药物。在此，我们研究了橙皮苷（HSN）对脂多糖（LPS）诱导的成纤维样滑膜（FLS）细胞的抗炎作用以及滑膜巨噬细胞的M1极化水平对抗原诱导的关节炎（AIA）的保护作用，以阐明炎症细胞因子和MMP的减少以及巨噬细胞活化的抑制。HSN对LPS诱导的炎症细胞因子的mRNA和蛋白表达的功能影响分别通过定量实时 PCR (qPCR) 或蛋白质印迹分析测定 FLS 细胞中的 MMP 和 MMP 以及 LPS 诱导的巨噬细胞 M1 和 M2 极化标记。通过腹膜内注射 HSN（20 毫克/公斤/天）或 LY294002（20 毫克/公斤/天）在 2 个月大的小鼠中产生 AIA。结果显示HSN显着抑制LPS诱导的炎症介质基因表达。此外，HSN治疗缓解了抗原诱导的关节炎，降低了FLS中MMP3、MMP9和MMP13的蛋白水平，并抑制了巨噬细胞向M1的极化。根据我们的分析结果，我们得出结论，HSN 具有显着的抗炎活性，并降低 MMP 在类风湿性关节炎中的潜力以及巨噬细胞向 M1 的极化程度。通过信号通路的研究，我们确定HSN抑制PI3K/AKT信号通路可能对类风湿性关节炎的进展具有治疗作用。
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis. Synovitis can cause joint injury by releasing inflammatory factors and metalloproteinases (MMPs). Therefore, it is necessary to find drugs that can control synovitis in the process of RA. Herein, we investigate the anti-inflammatory effect of Hesperidin (HSN) on fibroblast-like synovial (FLS) cells induced by lipopolysaccharide (LPS) and the protective action of M1 polarization level of synovial macrophages on antigen-induced arthritis (AIA) in order to elucidate the reduction of inflammatory cytokines and MMPs and the inhibition of macrophage activation.The functional effect of HSN on LPS-induced mRNA and protein expressions of inflammatory cytokines and MMPs in FLS cells as well as on LPS-induced macrophage M1 and M2 polarization markers was determined by quantitative real-time PCR (qPCR) or Western blot analyses, respectively. AIA in 2-month-old mice was generated using intraperitoneal injection with HSN (20 mg/kg/day) or LY294002 (20 mg/kg/day). The results show HSN significantly inhibited the LPS-induced gene expression of the inflammatory mediators. Furthermore, treatment with HSN relieved the antigen-induced arthritis and reduced the protein levels of MMP3, MMP9, and MMP13 in FLS and inhibited the polarization of macrophages to M1. Based on the results of our analyses, we concluded that HSN has significant anti-inflammatory activities and reduces the potential of MMPs in rheumatoid arthritis and the degree of polarization of macrophages to M1. Through the study of signaling pathways, we established that the inhibition of the PI3K/AKT signaling pathway by HSN may show therapeutic effects in the progression of rheumatoid arthritis.