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Circulating Plasma Extracellular Vesicles from Septic Mice Induce Inflammation via MicroRNA- and TLR7-Dependent Mechanisms.
J Immunol. 2018 12 01; 201(11):3392-3400.JI

Abstract

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) × 1010 versus (0.93 ± 0.14) × 1010/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-α, IL-1β, 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.

Authors+Show Affiliations

Translational Research Program, Department of Anesthesiology and Center for Shock Trauma Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, People's Republic of China; and.Translational Research Program, Department of Anesthesiology and Center for Shock Trauma Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201.Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742.Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742.Translational Research Program, Department of Anesthesiology and Center for Shock Trauma Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201; wchao@som.umaryland.edu lzou@som.umaryland.edu.Translational Research Program, Department of Anesthesiology and Center for Shock Trauma Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201; wchao@som.umaryland.edu lzou@som.umaryland.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30355788

Citation

Xu, Jinjin, et al. "Circulating Plasma Extracellular Vesicles From Septic Mice Induce Inflammation Via MicroRNA- and TLR7-Dependent Mechanisms." Journal of Immunology (Baltimore, Md. : 1950), vol. 201, no. 11, 2018, pp. 3392-3400.
Xu J, Feng Y, Jeyaram A, et al. Circulating Plasma Extracellular Vesicles from Septic Mice Induce Inflammation via MicroRNA- and TLR7-Dependent Mechanisms. J Immunol. 2018;201(11):3392-3400.
Xu, J., Feng, Y., Jeyaram, A., Jay, S. M., Zou, L., & Chao, W. (2018). Circulating Plasma Extracellular Vesicles from Septic Mice Induce Inflammation via MicroRNA- and TLR7-Dependent Mechanisms. Journal of Immunology (Baltimore, Md. : 1950), 201(11), 3392-3400. https://doi.org/10.4049/jimmunol.1801008
Xu J, et al. Circulating Plasma Extracellular Vesicles From Septic Mice Induce Inflammation Via MicroRNA- and TLR7-Dependent Mechanisms. J Immunol. 2018 12 1;201(11):3392-3400. PubMed PMID: 30355788.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Circulating Plasma Extracellular Vesicles from Septic Mice Induce Inflammation via MicroRNA- and TLR7-Dependent Mechanisms. AU - Xu,Jinjin, AU - Feng,Yan, AU - Jeyaram,Anjana, AU - Jay,Steven M, AU - Zou,Lin, AU - Chao,Wei, Y1 - 2018/10/24/ PY - 2018/07/19/received PY - 2018/09/21/accepted PY - 2018/10/26/pubmed PY - 2019/8/6/medline PY - 2018/10/26/entrez SP - 3392 EP - 3400 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 201 IS - 11 N2 - 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) × 1010 versus (0.93 ± 0.14) × 1010/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-α, IL-1β, 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/30355788/Circulating_Plasma_Extracellular_Vesicles_from_Septic_Mice_Induce_Inflammation_via_MicroRNA__and_TLR7_Dependent_Mechanisms_ DB - PRIME DP - Unbound Medicine ER -