Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS).
Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS).
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DOI：
10.1084/jem.20102049
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发表时间：
2011-03-14
期刊：
影响因子：
--
通讯作者：
Siegel RM
中科院分区：
文献类型：
--
作者：
Bulua AC;Simon A;Maddipati R;Pelletier M;Park H;Kim KY;Sack MN;Kastner DL;Siegel RM
在健康细胞中，线粒体呼吸产生的活性氧是促炎细胞因子产生的最佳条件，在自身炎症性疾病患者的细胞中，活性氧水平升高。活性氧（ROS）在炎症和宿主防御中发挥着既定的作用，因为它们杀死细胞内细菌，并已被证明可以激活NLRP3炎症小体。在这里，我们发现线粒体呼吸产生的ROS对于正常脂多糖（LPS）驱动的几种促炎细胞因子的产生和肿瘤坏死因子受体相关周期性综合征（trap）患者细胞对LPS的反应性增强很重要，trap是一种由1型TNF受体（TNFR1）错义突变引起的自身炎症性疾病。我们发现小鼠胚胎成纤维细胞和携带trap相关TNFR1突变的人类免疫细胞中ROS基线升高。多种抗氧化剂抑制lps诱导的MAPK磷酸化和炎症细胞因子的产生。然而，gp91phox和p22phox还原的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基在炎症细胞因子的产生中是不可缺少的，这表明NADPH氧化酶不是促炎ROS的来源。TNFR1突变细胞表现出线粒体功能改变，氧化能力增强，线粒体ROS生成增强，在trap患者和健康对照的细胞中，LPS刺激后，线粒体ROS的药物阻断有效地减少了炎症细胞因子的产生。这些发现表明，线粒体ROS可能是trap和其他炎症性疾病的新治疗靶点。
ROS generated by mitochondrial respiration are needed for optimal proinflammatory cytokine production in healthy cells, and are elevated in cells from patients with an autoinflammatory disorder. Reactive oxygen species (ROS) have an established role in inflammation and host defense, as they kill intracellular bacteria and have been shown to activate the NLRP3 inflammasome. Here, we find that ROS generated by mitochondrial respiration are important for normal lipopolysaccharide (LPS)-driven production of several proinflammatory cytokines and for the enhanced responsiveness to LPS seen in cells from patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), an autoinflammatory disorder caused by missense mutations in the type 1 TNF receptor (TNFR1). We find elevated baseline ROS in both mouse embryonic fibroblasts and human immune cells harboring TRAPS-associated TNFR1 mutations. A variety of antioxidants dampen LPS-induced MAPK phosphorylation and inflammatory cytokine production. However, gp91phox and p22phox reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits are dispensable for inflammatory cytokine production, indicating that NADPH oxidases are not the source of proinflammatory ROS. TNFR1 mutant cells exhibit altered mitochondrial function with enhanced oxidative capacity and mitochondrial ROS generation, and pharmacological blockade of mitochondrial ROS efficiently reduces inflammatory cytokine production after LPS stimulation in cells from TRAPS patients and healthy controls. These findings suggest that mitochondrial ROS may be a novel therapeutic target for TRAPS and other inflammatory diseases.
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影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
4.8
作者：
Li, NY;Ragheb, K;Robinson, JP
通讯作者：
Robinson, JP
影响因子：
15.9
作者：
Landmesser, U;Dikalov, S;Harrison, DG
通讯作者：
Harrison, DG
影响因子：
4.6
作者：
Filippin, L. I.;Vercelino, R.;Xavier, R. M.
通讯作者：
Xavier, R. M.