Extracellular RNA Sensing Mediates Inflammation and Organ Injury in a Murine Model of Polytrauma.
Extracellular RNA Sensing Mediates Inflammation and Organ Injury in a Murine Model of Polytrauma.
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DOI：
10.4049/jimmunol.2300103
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发表时间：
2023-06-15
期刊：
影响因子：
--
通讯作者：
Chao W
中科院分区：
文献类型：
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作者：
Suen AO;Chen F;Wang S;Li Z;Zhu J;Yang Y;Conn O;Lopez K;Cui P;Wechsler L;Cross A;Fiskum G;Kozar R;Hu P;Miller C;Zou L;Williams B;Chao W
严重创伤可导致明显的全身炎症和多脏器损伤。细胞外(EX)核酸等内源性驱动因子可能在介导先天免疫反应和下游发病机制中发挥作用。在这里，我们探讨了血浆exRNA在炎症和器官损伤中的作用及其在多发伤小鼠模型中的传感机制。我们发现，严重的多发性创伤--骨折、肌肉挤压伤和肠缺血--导致小鼠血浆exRNA显著增加，全身炎症和多器官损伤。用RNAseq分析小鼠和人类的血浆RNA图谱显示，在严重创伤后，miRNAs占主导地位，并且许多miRNAs的表达存在显著差异。从创伤小鼠分离的血浆exRNA诱导巨噬细胞产生剂量依赖的细胞因子，这种作用在TLR7缺陷的细胞中几乎被取消，但在TLR3缺陷的细胞中没有变化。此外，针对选定的促炎miRNAs的RNase或特异性miRNA抑制剂，即miR-7a-5p、miR-142、let-7j、miR-802和miR-146a-5p，分别可取消或减弱创伤血浆exRNA诱导的细胞因子的产生。基于细胞因子读数的一组miRNAs的生物信息学分析表明，在miRNA模拟诱导的细胞因子和补体产生中，高尿苷丰度(>；40%)是一个可靠的预测因子。与WT组相比，TLR7KO组小鼠多发伤后血浆细胞因子风暴减轻，肺、肝损伤减轻。这些数据表明，严重损伤小鼠的内源性血浆exRNA和尿苷丰度高的ex-miRNAs被证明是高度促炎的。TLR7对血浆exRNA和ex-miRNAs的感知可激活先天免疫反应，在创伤后的炎症和器官损伤中发挥作用。
Severe traumatic injury leads to marked systemic inflammation and multi-organ injury. Endogenous drivers such as extracellular (ex) nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma exRNA and its sensing mechanism in inflammation and organ injury in a murine model polytrauma. We found that severe polytrauma – bone fracture, muscle crush injury, and bowel ischemia – induced a marked increase in plasma exRNA, systemic inflammation, and multi-organ injury in mice. Plasma RNA profiling with RNAseq in mice and humans revealed a dominant presence of miRNAs and marked differential expression of numerous miRNAs after severe trauma. Plasma exRNA isolated from trauma mice induced a dose-dependent cytokine production in macrophages, which was almost abolished in TLR7-deficient cells, but unchanged in TLR3-deficient cells. Moreover, RNase or specific miRNA inhibitors against the selected proinflammatory miRNAs, i.e., miR-7a-5p, miR-142, let-7j, miR-802, and miR-146a-5p, abolished or attenuated trauma plasma exRNA-induced cytokine production, respectively. Bioinformatics analyses of a group of miRNAs based on cytokine readouts revealed that high uridine abundance (>40%) is a reliable predictor in miRNA mimic-induced cytokine and complement productions. Finally, compared to WT, TLR7 KO mice had attenuated plasma cytokine storm, and reduced lung and hepatic injury after polytrauma. These data suggest that endogenous plasma exRNA of severely injured mice and ex-miRNAs with high uridine abundance prove to be highly proinflammatory. TLR7 sensing of plasma exRNA and ex-miRNAs activates innate immune responses and plays a role in inflammation and organ injury after trauma.
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影响因子：
--
作者：
Shimada BK;Yang Y;Zhu J;Wang S;Suen A;Kronstadt SM;Jeyaram A;Jay SM;Zou L;Chao W
通讯作者：
Chao W
影响因子：
4.6
作者：
Caserta S;Kern F;Cohen J;Drage S;Newbury SF;Llewelyn MJ
通讯作者：
Llewelyn MJ
影响因子：
4.7
作者：
Goelz, Christina;Kirchhoff, Florian Paul;Schaefert, Michael K. E.
通讯作者：
Schaefert, Michael K. E.
影响因子：
14.9
作者：
Ru Y;Kechris KJ;Tabakoff B;Hoffman P;Radcliffe RA;Bowler R;Mahaffey S;Rossi S;Calin GA;Bemis L;Theodorescu D
通讯作者：
Theodorescu D
DOI：
10.4049/jimmunol.1700730
发表时间：
2017-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Feng Y;Zou L;Yan D;Chen H;Xu G;Jian W;Cui P;Chao W
通讯作者：
Chao W