Redox homeostasis involvement in the pharmacological effects of metformin in systemic lupus erythematosus.
Redox homeostasis involvement in the pharmacological effects of metformin in systemic lupus erythematosus.
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DOI：
10.1089/ars.2021.0070
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发表时间：
2021-10
影响因子：
6.6
通讯作者：
X. Teng;Josephine Brown;L. Morel
中科院分区：
文献类型：
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作者：
X. Teng;Josephine Brown;L. Morel
二甲双胍已被建议用于系统性红斑狼疮（SLE）的治疗。二甲双胍的主要靶点是线粒体中的电子传递链复合体I，它与免疫细胞的氧化还原稳态有关，在自身免疫性疾病的发病机制中起着关键作用。这篇综述解决了二甲双胍对狼疮的有益作用是否可能是由于平衡氧化还原状态的恢复的证据和知识差距。最新进展：在轻度至中度疾病活动性SLE患者的临床试验和小鼠临床前研究中，二甲双胍提供了令人鼓舞的结果。实现这种治疗效果的机制在很大程度上是未知的。二甲双胍以特定的方式调节氧化还原稳态。多种细胞类型导致SLE，有证据表明T细胞和中性粒细胞线粒体氧化应激增加。主要的知识空白是二甲双胍的功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，以及它是否对应于一种特定的机制？最后，识别生物标志物来预测治疗结果将具有很大的价值。未来方向：机制研究必须解决二甲双胍的情境依赖性药理作用。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。
SIGNIFICANCE 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. Recent Advances: 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. CRITICAL ISSUES 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. FUTURE DIRECTIONS 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.