RNA Externalized by Neutrophil Extracellular Traps Promotes Inflammatory Pathways in Endothelial Cells.
RNA Externalized by Neutrophil Extracellular Traps Promotes Inflammatory Pathways in Endothelial Cells.
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DOI：
10.1002/art.41796
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Kaplan MJ
中科院分区：
文献类型：
--
作者：
Blanco LP;Wang X;Carlucci PM;Torres-Ruiz JJ;Romo-Tena J;Sun HW;Hafner M;Kaplan MJ
中性粒细胞胞外陷阱(Net)是由中性粒细胞颗粒蛋白结合的核物质组成的胞外晶格。Net可能在自身免疫性疾病如系统性红斑狼疮(SLE)的发生和严重程度中发挥致病作用，至少部分是通过氧化的免疫刺激DNA外化诱导I型干扰素(IFN)反应。SLE促炎中性粒细胞(低密度粒细胞；LDGs)的一个独特亚群显示出增强的形成促炎网络的能力，从而破坏血管系统。我们评估了净结合的RNA是否可以促进内皮细胞的炎症反应，以及介导这一效应的途径。定量检测新合成的RNA和总RNA在HC和狼疮网络中的表达。对内皮细胞摄取净结合的RNA和下游诱导I型干扰素反应的能力进行了量化。对Net中存在的RNA进行测序，并检测特定的小RNA对内皮I型干扰素通路的诱导作用。Net排出被内皮细胞内化的RNA，当网络结合的核酸被氧化时，这一点得到加强，尤其是在狼疮LDG Net中。内皮细胞对净结合RNA的内化依赖于内体TLRs和肌动蛋白细胞骨架以及诱导的I型干扰素刺激基因(ISGs)。这种ISG的诱导依赖于网络相关的miR-let7b，这是一种在LDG Net中高水平表达的小RNA，它作为TLR7激动剂。这些结果突出了在Net中外化的小RNA在诱导血管细胞的促炎反应中的作用被低估，这与狼疮血管病变有关。
Neutrophil extracellular traps (NETs) are extracellular lattices composed of nucleic material bound to neutrophil granule proteins. NETs may play pathogenic roles in development and severity of autoimmune diseases such as systemic lupus erythematosus (SLE), at least in part, through induction of type I interferon (IFN) responses via externalization of oxidized immunostimulatory DNA. A distinct subset of SLE proinflammatory neutrophils (low density granulocytes; LDGs) displays enhanced ability to form proinflammatory NETs that damage the vasculature. We assessed whether NET-bound RNA can contribute to inflammatory responses in endothelial cells and the pathways that mediate this effect. Expression of newly-synthesized and total RNA was quantified in HC and lupus NETs. The ability of endothelial cells to take up NET-bound RNA and downstream induction of type I IFN responses was quantified. RNAs present in NETs were sequenced and specific small RNAs were tested for induction of endothelial type I IFN pathways. NETs extruded RNA that was internalized by endothelial cells and this was enhanced when NET-bound nucleic acids were oxidized, particularly in lupus LDG NETs. Internalization of NET-bound RNA by endothelial cells was dependent on endosomal TLRs and the actin cytoskeleton and induced type I IFN stimulated genes (ISGs). This ISG induction was dependent on NET-associated miR-let7b, a small RNA expressed at higher levels in LDG NETs, which acted as a TLR7 agonist. These results highlight underappreciated roles for small RNAs externalized in NETs in the induction of proinflammatory responses in vascular cells, with implications to lupus vasculopathy.
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影响因子：
8.8
作者：
Chen PY;Qin L;Barnes C;Charisse K;Yi T;Zhang X;Ali R;Medina PP;Yu J;Slack FJ;Anderson DG;Kotelianski V;Wang F;Tellides G;Simons M
通讯作者：
Simons M
let-7a 和 let-7b 对氧化低密度脂蛋白诱导的内皮细胞损伤的保护作用。
影响因子：
3.7
作者：
Bao MH;Zhang YW;Lou XY;Cheng Y;Zhou HH
通讯作者：
Zhou HH
DOI：
10.1038/nrrheum.2011.132
发表时间：
2011-09-27
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.6
作者：
Kawashima T;Ikari N;Kouchi T;Kowatari Y;Kubota Y;Shimojo N;Tsuji NM
通讯作者：
Tsuji NM
影响因子：
24.8
作者：
Carmona-Rivera, Carmelo;Carlucci, Philip M.;Kaplan, Mariana J.
通讯作者：
Kaplan, Mariana J.