Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA.
Antioxid Redox Signal. 2022 Mar;36(7-9):462-479. doi: 10.1089/ars.2021.0070. Epub 2022 Jan 4.
Metformin has been proposed as a treatment for systemic lupus erythematosus (SLE). The primary target of metformin, the electron transport chain complex I in the mitochondria, is associated with redox homeostasis in immune cells, which plays a critical role in the pathogenesis of autoimmune diseases. This review addresses the evidence and knowledge gaps on whether a beneficial effect of metformin in lupus may be due to a restoration of a balanced redox state. Clinical trials in SLE patients with mild-to-moderate disease activity and preclinical studies in mice have provided encouraging results for metformin. The mechanism by which this therapeutic effect was achieved is largely unknown. Metformin regulates redox homeostasis in a context-specific manner. Multiple cell types contribute to SLE, with evidence of increased mitochondrial oxidative stress in T cells and neutrophils. The major knowledge gaps are whether the efficacy of metformin is linked to a restored redox homeostasis in the immune system, and if it does, in which cell types it occurs? We also need to know which patients may have a better response to metformin, and whether it corresponds to a specific mechanism? Finally, the identification of biomarkers to predict treatment outcomes would be of great value. Mechanistic studies must address the context-dependent pharmacological effects of metformin. Multiple cell types as well as a complex disease etiology should be considered. These studies must integrate the rapid advances made in understanding how metabolic programs direct the effector functions of immune cells. 36, 462-479.
二甲双胍被提议用于治疗系统性红斑狼疮 (SLE)。二甲双胍的主要靶点是线粒体中的电子传递链复合物 I，它与免疫细胞中的氧化还原稳态有关，而氧化还原稳态在自身免疫性疾病的发病机制中起着关键作用。本文综述了二甲双胍在狼疮中是否可能通过恢复平衡的氧化还原状态而产生有益作用的证据和知识空白。 对于疾病活动度轻中度的 SLE 患者的临床试验以及在小鼠中的临床前研究为二甲双胍提供了令人鼓舞的结果。这种治疗效果的机制尚不清楚。二甲双胍以特定于上下文的方式调节氧化还原稳态。多种细胞类型参与 SLE，T 细胞和中性粒细胞中存在线粒体氧化应激增加的证据。 主要的知识空白是二甲双胍的疗效是否与免疫系统中氧化还原稳态的恢复有关，如果是，它发生在哪些细胞类型中？我们还需要知道哪些患者可能对二甲双胍有更好的反应，以及它是否对应于特定的机制？最后，鉴定预测治疗结果的生物标志物将具有重要价值。 必须对二甲双胍的基于上下文的药理作用进行机制研究。应考虑多种细胞类型以及复杂的疾病病因。这些研究必须整合在理解代谢程序如何指导免疫细胞的效应功能方面取得的快速进展。 36, 462-479.
