Mitochondrial DNA has a pro-inflammatory role in AMD.
Mitochondrial DNA has a pro-inflammatory role in AMD.
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线粒体 DNA 在 AMD 中具有促炎作用。
DOI：
10.1016/j.bbamcr.2015.08.012
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Vavvas DG
中科院分区：
文献类型：
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作者：
Dib B;Lin H;Maidana DE;Tian B;Miller JB;Bouzika P;Miller JW;Vavvas DG
年龄相关性黄斑变性（AMD）是工业化国家老年人不可逆失明的主要原因，越来越多的证据支持慢性炎症在其发病机制中的作用。线粒体DNA （mtDNA）最近被报道在阿尔茨海默氏症和心力衰竭等多种疾病中具有促炎作用。在这里，我们报道细胞内mtDNA诱导ARPE-19细胞分泌IL-6和IL-8，这两种炎症细胞因子一直与AMD的发病和进展相关。诱导与mtDNA的大小有关，而与特定的序列无关。氧化应激在AMD的发展中起着重要作用，我们的研究结果表明mtDNA在氧化时更有效地诱导IL-6和IL-8。细胞因子的诱导是由STING（干扰素基因刺激因子）和NF-κB介导的，使用特异性抑制剂（分别为siRNA和Bay 11-7082）可以消除细胞因子的反应。最后，mtDNA启动NLRP3炎性体，并弱激活它，如caspase-1激活和成熟的IL-1β分泌。这项研究有助于我们了解mtDNA在AMD发病机制中的潜在促炎作用。
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly of industrialized nations, and there is increasing evidence to support a role for chronic inflammation in its pathogenesis. Mitochondrial DNA (mtDNA) has been recently reported to be pro-inflammatory in various diseases such as Alzheimer’s and heart failure. Here, we report that intracellular mtDNA induces ARPE-19 cells to secrete IL-6 and IL-8, inflammatory cytokines that have consistently been associated with AMD onset and progression. The induction was dependent on the size of mtDNA, but not on specific sequence. Oxidative stress plays a major role in the development of AMD, and our findings indicate that mtDNA induces IL-6 and IL-8 more potently when oxidized. Cytokine induction was mediated by STING (Stimulator of Interferon Genes) and NF-κB as evidenced by abrogation of the cytokine response with use of specific inhibitors (siRNA and Bay 11–7082, respectively). Finally, mtDNA primed the NLRP3 inflammasome and weakly activated it as shown by caspase-1 activation and mature IL-1β secretion. This study contributes to our understanding of the potential pro-inflammatory role of mtDNA in the pathogenesis of AMD.