College of Basic Medical Sciences, Zhejiang Chinese Medical University, 548 Bingwen Road, Hangzhou, Zhejiang, 310053, China.
The Third Affiliated Hospital of Zhejiang Chinese Medical University, 219 Moganshan Road, Hangzhou, Zhejiang, 310014, China.
Free Radic Biol Med. 2021 Feb 1;163:210-219. doi: 10.1016/j.freeradbiomed.2020.12.006. Epub 2020 Dec 19.
There exist close relationships among oxidative stress, dyslipidaemia, inflammation, and autoimmune response in patients with systemic lupus erythematosus (SLE). Dysfunction and/or dysregulation of immunocytes is one of the major characteristics of SLE pathogenesis. Lipids play many important roles in biological processes and cellular functions. We hypothesized that oxidative stress-induced aberrant lipid metabolism and integrity presented in immunocytes is one of the early events in patients, thereby leading to enhanced production of IgG autoantibodies and cytokines. Herein, shotgun lipidomics was employed for quantitative analysis of cellular lipidomes in peripheral blood mononuclear cells (PBMC) both freshly isolated from SLE patients and cultured with treatment. The levels of IgG autoantibodies and cytokines in cell culture media and serum samples from lupus-prone mice treated with a natural, powerful antioxidant isotonix OPC-3 were measured by ELISA kits. IgG antibody deposition in glomeruli of the mice was determined by immunofluorescence analysis. Lipidomics analysis of PBMC from 33 SLE patients and 28 healthy controls revealed aberrant lipid metabolism in PBMC from the patients. The changes included significantly reduced plasmalogens, markedly increased lysophospholipids, altered phosphatidylserines, and accumulated 4-hydroxyalkenals. These alterations of lipids in SLE PBMC could be significantly corrected after cultured with the antioxidant in vitro. Parallel to the IgG antibody deposition in glomeruli, the concentrations of cytokines (i.e., IL-10, IL-6, and TNF-α) and autoantibodies (e.g., IgG antiphospholipid and anti-dsDNA antibodies) in culture medium and serum samples from the mice after treatment with the antioxidant were also significantly reduced compared with those of the SLE group. The results clearly demonstrated that correction of the aberrant lipid metabolism led to inhibition of the autoimmune reactions of PBMC after reduction of the increased oxidative stress. The current study also revealed potential drug treatment of SLE with lesser adverse effects through reducing the aberrant lipid metabolism with an effective antioxidant.
在系统性红斑狼疮 (SLE) 患者中，氧化应激、血脂异常、炎症和自身免疫反应之间存在密切关系。免疫细胞的功能障碍和/或失调是 SLE 发病机制的主要特征之一。脂质在生物过程和细胞功能中发挥着许多重要作用。我们假设，免疫细胞中氧化应激诱导的异常脂质代谢和完整性的丧失是患者早期的事件之一，从而导致 IgG 自身抗体和细胞因子的产生增加。在此，我们采用 shotgun 脂质组学方法对新鲜分离的 SLE 患者和经治疗培养的外周血单个核细胞 (PBMC) 的细胞脂质组进行定量分析。通过 ELISA 试剂盒测定经天然强效抗氧化剂 isotonix OPC-3 处理的狼疮易感小鼠细胞培养物上清液和血清中 IgG 自身抗体和细胞因子的水平。通过免疫荧光分析测定小鼠肾小球中 IgG 抗体的沉积。对 33 名 SLE 患者和 28 名健康对照者的 PBMC 进行脂质组学分析，结果显示患者 PBMC 中存在异常的脂质代谢。这些变化包括明显减少的质体，显著增加的溶血磷脂，改变的磷脂酰丝氨酸和积累的 4-羟基烯醛。这些 SLE PBMC 中的脂质变化在用抗氧化剂体外培养后可以得到显著纠正。与肾小球中 IgG 抗体沉积平行的是，用抗氧化剂处理后，小鼠培养物上清液和血清样本中的细胞因子 (如 IL-10、IL-6 和 TNF-α) 和自身抗体 (如 IgG 抗磷脂和抗 dsDNA 抗体) 的浓度也明显低于 SLE 组。结果清楚地表明，在氧化应激增加得到缓解后，纠正异常脂质代谢导致 PBMC 自身免疫反应的抑制。本研究还揭示了通过减少异常脂质代谢，用一种有效的抗氧化剂治疗 SLE，具有较少的不良反应的潜在药物治疗方法。
