关键词: G-protein-coupled receptors Mitochondria Neurodegeneration Neuroinflammation adenosine A(2A) receptor adenosine A(3) receptor

来  源:   DOI:10.1016/j.mito.2024.101934

Abstract:
A hallmark of neuroinflammatory disorders is mitochondrial dysfunction. Nevertheless, the transcriptional changes underlying this alteration are not well-defined. Microglia activation, a decrease in mitochondrion biogenesis and a subsequent alteration of the redox are common factors in diseases coursing with neuroinflammation. In the last two decades, components of the adenosinergic system have been proposed as potential therapeutic targets to combat neuroinflammation. In this research, we analyzed by RNAseq the gene expression in activated microglia treated with an adenosine A2A receptor antagonist, SCH 582561, and/or an A3 receptor agonist, 2-Cl-IB-MECA, since these receptors are deeply related to neurodegeneration and inflammation. The analysis was focused on genes related to inflammation and REDOX homeostasis. It was detected that in the three conditions (microglia treated with 2-Cl-IB-MECA, SCH 582561, and their combination) more than 40 % of the detected genes codified by the mitochondrial genome were differentially expressed (FDR < 0.05) (14/34, 16/34, and 13/34) respectively, being almost all of them (>85 %) upregulated in the microglia treated with adenosinergic compounds. Also, we analyzed the differential expression of genes related to mitochondrial function and oxidative stress codified by the nuclear genome. Additionally, we evaluated the oxygen consumption rate (OCR) of mitochondria in microglia treated with LPS and IFN-γ, both alone and in combination with adenosinergic compounds. The data showed an improvement in mitochondrial function with the antagonist of the adenosine A2A receptor, compared to the effects of pro-inflammatory stimulus, confirming a functional effect consistent with the RNAseq data.
摘要:
神经炎性疾病的标志是线粒体功能障碍。然而,这种改变背后的转录变化并不明确。小胶质细胞激活,线粒体生物发生的减少和随后氧化还原的改变是伴随神经炎症的疾病的常见因素。在过去的二十年里,腺苷系统的成分已被提出作为对抗神经炎症的潜在治疗靶点。在这项研究中,我们通过RNAseq分析了用腺苷A2A受体拮抗剂处理的活化小胶质细胞的基因表达,SCH582561和/或A3受体激动剂,2-Cl-IB-MECA,因为这些受体与神经变性和炎症密切相关。分析集中在与炎症和REDOX稳态相关的基因上。检测到在三种条件下(用2-Cl-IB-MECA处理的小胶质细胞,SCH582561和组合)线粒体基因组编码的检测基因中有40%以上差异表达(FDR<0.05)(分别为14/34、16/34和13/34),在用腺苷能化合物处理的小胶质细胞中几乎所有这些(>85%)都上调。此外,我们分析了与核基因组编码的线粒体功能和氧化应激相关的基因的差异表达。此外,我们评估了用LPS和IFN-γ处理的小胶质细胞中线粒体的耗氧率(OCR),单独和与腺苷能化合物联合使用。数据显示,腺苷A2A受体拮抗剂可改善线粒体功能,与促炎刺激的作用相比,确认与RNAseq数据一致的功能效应。
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