Mitochondrial DNA Is a Pro-Inflammatory Damage-Associated Molecular Pattern Released During Active IBD
Mitochondrial DNA Is a Pro-Inflammatory Damage-Associated Molecular Pattern Released During Active IBD
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DOI：
10.1093/ibd/izy095
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发表时间：
2018-10-01
影响因子：
4.9
通讯作者：
Ho, Gwo-tzer
中科院分区：
文献类型：
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作者：
Boyapati, Ray K.;Dorward, David A.;Ho, Gwo-tzer
背景：由于共同的进化起源，线粒体DNA（mtDNA）与具有免疫原性的细菌DNA有许多相似之处。MtDNA被认为是一种促炎性损伤相关分子模式（DAMP），在几种炎性疾病中具有致病作用。我们假设mtDNA在活动性疾病期间释放，作为炎症性肠病（IBD）中的关键促炎因子。方法：在2014年至2015年期间，我们收集了97名前瞻性招募的IBD患者（67名溃疡性结肠炎[UC]和30名克罗恩病[CD]）和40名非IBD对照组在采样后2小时内分离的血浆。我们使用定量聚合酶链反应（扩增线粒体COXIII/ND 2基因）测量循环mtDNA，并在葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎中进行测量。我们使用质谱法检测游离血浆线粒体甲酰化肽。结果：UC和CD患者血浆mtDNA水平均高于非IBD对照组（P <0.0001），UC患者血浆mtDNA水平高于非IBD对照组（P < 0.0001），CD患者血浆mtDNA水平高于非IBD对照组（P < 0.0001）。这些水平与血液（C-反应蛋白、白蛋白、白色细胞计数）、临床和内镜严重程度标志物以及疾病活动性显著相关。在活动性UC中，我们在血浆中鉴定了5种线粒体甲酰化肽（最丰富的是具有已知化学引诱物功能的fMMYALF）。我们观察到炎症UC粘膜中的线粒体损伤和显着更高的粪便MtDNA水平（与非IBD对照组相比[P < 0.0001]），这支持肠粘膜线粒体DAMP释放为主要来源。与此同时，血浆mtDNA水平在诱导急性DSS结肠炎期间升高，并且与更严重的结肠炎相关（P < 0.05）。活动期IBD中UC和CD固有层炎性细胞TLR 9阳性率显著高于对照组（P < 0.05）。线粒体DNA是一种潜在的机制生物标志物，我们的数据表明，mtDNA-TLR 9作为IBD的治疗靶点。
Background: Due to common evolutionary origins, mitochondrial DNA (mtDNA) shares many similarities with immunogenic bacterial DNA. MtDNA is recognized as a pro-inflammatory damage-associated molecular pattern (DAMP) with a pathogenic role in several inflammatory diseases. We hypothesised that mtDNA is released during active disease, serving as a key pro-inflammatory factor in inflammatory bowel disease (IBD).Methods: Between 2014 and 2015, we collected plasma separated within 2 hours of sampling from 97 prospectively recruited IBD patients (67 ulcerative colitis [UC] and 30 Crohn's disease [CD]) and 40 non-IBD controls. We measured circulating mtDNA using quantitative polymerase chain reaction (amplifying mitochondria COXIII/ND2 genes) and also in mouse colitis induced by dextran sulfate-sodium (DSS). We used a mass spectometry approach to detect free plasma mitochondrial formylated peptides. Furthermore, we examined for mitochondrial damage using electron microscopy (EM) and TLR9 expression, the target for mtDNA, in human intestinal IBD mucosa.Results: Plasma mtDNA levels were increased in UC and CD (both P < 0.0001) compared with non-IBD controls. These levels were significantly correlated to blood (C-reactive protein, albumin, white cell count), clinical and endoscopic markers of severity, and disease activity. In active UC, we identified 5 mitochondrial formylated peptides (the most abundant being fMMYALF with known chemoattractant function) in plasma. We observed mitochondrial damage in inflamed UC mucosa and significantly higher fecal MtDNA levels (vs non-IBD controls [P < 0.0001]), which supports gut mucosal mitochondrial DAMP release as the primary source. In parallel, plasma mtDNA levels increased during induction of acute DSS colitis and were associated with more severe colitis (P < 0.05). In active IBD, TLR9+ lamina propria inflammatory cells were significantly higher in UC and CD compared with controls (P < 0.05).Conclusions: We present the first evidence to show that mtDNA is released during active IBD. MtDNA is a potential mechanistic biomarker, and our data point to mtDNA-TLR9 as a therapeutic target in IBD.