Bioactive Plasma Mitochondrial DNA Is Associated With Disease Progression in Scleroderma-Associated Interstitial Lung Disease.
Bioactive Plasma Mitochondrial DNA Is Associated With Disease Progression in Scleroderma-Associated Interstitial Lung Disease.
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DOI：
10.1002/art.41418
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Herzog EL
中科院分区：
文献类型：
--
作者：
Ryu C;Walia A;Ortiz V;Perry C;Woo S;Reeves BC;Sun H;Winkler J;Kanyo JE;Wang W;Vukmirovic M;Ristic N;Stratton EA;Meena SR;Minasyan M;Kurbanov D;Liu X;Lam TT;Farina G;Gomez JL;Gulati M;Herzog EL
SSc-ILD的特征为临床结局可变、先天免疫模式识别受体（PRR）激活和表达αSMA的肌成纤维细胞蓄积。这些实体与线粒体DNA（mtDNA）（细胞内DNA敏感PRRs TLR 9和cGAS-STING的内源性配体）的关联尚未确定。用合成CpG DNA处理来自正常供体（NHLF）和SSc-ILD外植体的人肺成纤维细胞，并使用人MT-ATP 6基因的qPCR测定αSMA表达和细胞外mtDNA。在两个独立的SSc-ILD队列和人口统计学匹配的对照组中评价血浆MT-ATP 6浓度。用市售HEK 293报告细胞评价对照和SSc-ILD血浆诱导TLR 9和cGAS-STING活化的能力。分别采用电化学发光法和ELISA法测定血浆I型干扰素、IL-6和氧化DNA浓度。通过液相色谱-质谱法评价从血浆沉淀的细胞外囊泡（EV）的MT-ATP 6浓度和蛋白质组学。CpG刺激后，NHLF和SSc-ILD成纤维细胞αSMA表达和MT-ATP 6释放增加。在两个SSc-ILD队列中，血浆mtDNA浓度增加，反映了抑制性下降，并且与TLR 9和cGAS-STING活化以及I型干扰素和IL-6表达正相关。血浆mtDNA不被氧化，并且由EV输送，其显示与多细胞起源一致的蛋白质组学谱。这些发现表明，在SSc-ILD中EV包裹的mtDNA、临床结局和细胞内DNA敏感PRR激活之间存在未被认识的联系。对这些相互作用的进一步研究可以促进对SSc-ILD和相关疾病的新机制和治疗见解。
SSc-ILD is characterized by variable clinical outcomes, activation of innate immune pattern recognition receptors (PRRs), and accumulation of αSMA expressing myofibroblasts. The association of these entities with mitochondrial DNA (mtDNA), an endogenous ligand for the intracellular DNA-sensing PRRs TLR9 and cGAS-STING, has yet to be determined. Human lung fibroblasts from normal donors (NHLFs) and SSc-ILD explants were treated with synthetic CpG DNA and assayed for αSMA expression and extracellular mtDNA using qPCR for the human MT-ATP6 gene. Plasma MT-ATP6 concentrations were evaluated in two independent SSc-ILD cohorts and demographically matched controls. The ability of control and SSc-ILD plasma to induce TLR9 and cGAS-STING activation was evaluated with commercially available HEK 293 reporter cells. Plasma concentrations of type I interferons, IL-6, and oxidized DNA were measured with using electrochemiluminescence and ELISA-based methods, respectively. Extracellular vesicles (EVs) precipitated from plasma were evaluated for MT-ATP6 concentrations and proteomics via liquid chromatography–mass spectrometry. NHLFs and SSc-ILD fibroblasts develop increased αSMA expression and MT-ATP6 release following CpG stimulation. Plasma mtDNA concentrations are increased in two SSc-ILD cohorts, reflective of ventilatory decline, and positively associated with both TLR9 and cGAS-STING activation as well as Type I interferon and IL-6 expression. Plasma mtDNA is not oxidized and is conveyed by EVs displaying a proteomics profile consistent with a multicellular origin. These findings demonstrate an unrecognized connection between EV-encapsulated mtDNA, clinical outcomes, and intracellular DNA-sensing PRR activation in SSc-ILD. Further study of these interactions could catalyze novel mechanistic and therapeutic insights into SSc-ILD and related disorders.
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影响因子：
4.9
作者：
Agarwal SK;Wu M;Livingston CK;Parks DH;Mayes MD;Arnett FC;Tan FK
通讯作者：
Tan FK
影响因子：
82.9
作者：
Du Y;Yamaguchi H;Wei Y;Hsu JL;Wang HL;Hsu YH;Lin WC;Yu WH;Leonard PG;Lee GR 4th;Chen MK;Nakai K;Hsu MC;Chen CT;Sun Y;Wu Y;Chang WC;Huang WC;Liu CL;Chang YC;Chen CH;Park M;Jones P;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
DOI：
10.1084/jem.20151876
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caielli S;Athale S;Domic B;Murat E;Chandra M;Banchereau R;Baisch J;Phelps K;Clayton S;Gong M;Wright T;Punaro M;Palucka K;Guiducci C;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
4.9
作者：
Christmann RB;Wooten A;Sampaio-Barros P;Borges CL;Carvalho CR;Kairalla RA;Feghali-Bostwick C;Ziemek J;Mei Y;Goummih S;Tan J;Alvarez D;Kass DJ;Rojas M;de Mattos TL;Parra E;Stifano G;Capelozzi VL;Simms RW;Lafyatis R
通讯作者：
Lafyatis R
影响因子：
--
作者：
Artlett, Carol M.;Sassi-Gaha, Sihem;Katsikis, Peter D.
通讯作者：
Katsikis, Peter D.