Circulating Plasma Extracellular Vesicles from Septic Mice Induce Inflammation via MicroRNA- and TLR7-Dependent Mechanisms
Circulating Plasma Extracellular Vesicles from Septic Mice Induce Inflammation via MicroRNA- and TLR7-Dependent Mechanisms
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DOI：
10.4049/jimmunol.1801008
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发表时间：
2018-12-01
影响因子：
4.4
通讯作者：
Chao, Wei
中科院分区：
文献类型：
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作者：
Xu, Jinjin;Feng, Yan;Chao, Wei
我们以前报道过一组宿主细胞microRNAs(miRNAs；miR-34a-5p、miR-122-5p、miR-145-5p、miR-146a-5p、miR-210-3p)在脓毒症期间释放到血液中，其中一些能够诱导补体激活、细胞因子产生和白细胞迁移。细胞外小泡(EVS)被认为是细胞外miRNA介导的细胞间通讯的载体。然而，血浆EVS及其相关的miRNAs在脓毒症中的生物学功能在很大程度上尚不清楚。在这项研究中，我们验证了以下假设：脓毒症患者的血浆EV是促炎的，EV相关的miRNAs负责EV诱导的细胞因子的产生。与假手术组相比，脓毒症小鼠血浆EVS略小(15 7+/-2比191+/-6 nm，p<；0.0001)，但更丰富[(1.6+/-0.14)×10(10)比(0.93+/-0.14)×10(10)/ml血浆，p<；0.003]。MiRNA阵列显示，在65个miRNAs中，有8个miRNAs的败血症EV比假EV高1.5倍，包括miR-126-3p、miR-122-5p、miR-146a-5p、miR-145-5p、miR-26a-5p、miR-150-5p、miR-222-3p和miR-181a-5p。脓毒症而不是假EV是促炎的，促进IL-6、TNF-α、IL-1β和MIP-2的产生。EVS的作用对多粘菌素B(一种内毒素抑制剂)具有耐药性，但可被针对miR-34a、miR-122和miR-146a的抗miR抑制剂显著抑制。此外，败血症EV诱导的细胞因子的产生在TLR7(-/-)或MyD88(-/-)细胞中减弱，但在TLR3(-/-)或Trif(-/-)细胞中保持不变。在体内，小鼠ip。注射败血症EVS后，MyD88(-/-)小鼠的腹膜中性粒细胞迁移明显减弱。综上所述，这些数据表明脓毒症动物的血浆EV在炎症中发挥重要作用，EV相关的miRNAs可能通过TLR7-MyD88信号介导细胞因子的产生。
We have previously reported that a group of host cellular microRNAs (miRNAs; miR-34a-5p, miR-122-5p, miR-145-5p, miR-146a-5p, miR-210-3p) are released into the blood during sepsis, some of which are capable of inducing complement activation, cytokine production, and leukocyte migration. Extracellular vesicles (EVs) have been proposed as vehicles for extracellular miRNA-mediated intercellular communication. However, the biological function of plasma EVs and the associated miRNAs in sepsis are largely unknown. In this study, we tested the hypothesis that plasma EVs in sepsis are proinflammatory and EV-associated miRNAs are responsible for EV-induced cytokine production. Compared with those of sham mice, the plasma EVs from septic mice were slightly smaller (157 +/- 2 versus 191 +/- 6 nm, p < 0.0001), but more abundant [(1.6 +/- 0.14) x 10(10) versus (0.93 +/- 0.14) x 10(10) /ml plasma, p < 0.003]. miRNA array revealed that among 65 miRNAs, 8 miRNAs exhibited > 1.5-fold increase in septic EVs compared with sham EVs, including miR-126-3p, miR-122-5p, miR-146a-5p, miR-145-5p, miR-26a-5p, miR-150-5p, miR-222-3p, and miR-181a-5p. Septic but not sham EVs were proinflammatory, promoting IL-6, TNF-alpha, IL-1 beta, and MIP-2 production. The effects of EVs were resistant to polymyxin B (an endotoxin inhibitor) but significantly inhibited by anti-miR inhibitors against miR-34a, miR-122, and miR-146a. Moreover, the septic EV-induced cytokine production was attenuated in TLR7(-/-) or MyD88(-/-) cells but remained the same in TLR3(-/-) or Trif(-/-) cells. In vivo, mice i.p. injected with septic EVs had marked peritoneal neutrophil migration, which was significantly attenuated in MyD88(-/-) mice. Taken together, these data demonstrate that plasma EVs of septic animals play an important role in inflammation, and EV-associated miRNAs likely mediate the cytokine production via TLR7-MyD88 signaling.