Mesenchymal Stem Cell-Derived Extracellular Vesicles Decrease Lung Injury in Mice
| Autor: | Jae Hoon Lee, Li Zhou, Hideya Kato, Hongli He, Antoine Monsel, Jae Won Lee, Shuling Hu, Qi Hao, Jeong H Park, Varun Gudapati |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
1.1 Normal biological development and functioning Immunology Acute Lung Injury Lung injury Leukotriene B4 Article 03 medical and health sciences Extracellular Vesicles Mice 0302 clinical medicine Stem Cell Research - Nonembryonic - Human Underpinning research In vivo Escherichia coli Pneumonia Bacterial 2.1 Biological and endogenous factors Immunology and Allergy Animals Humans Aetiology Lung Escherichia coli Infections Gene knockdown Leukotriene Chemistry Mesenchymal stem cell Bacterial Mesenchymal Stem Cells Pneumonia respiratory system Stem Cell Research Antimicrobial Molecular biology In vitro Leukotriene C4 Infectious Diseases RAW 264.7 Cells Quinolines lipids (amino acids peptides and proteins) Efflux Multidrug Resistance-Associated Proteins Propionates 030215 immunology |
| Zdroj: | J Immunol Journal of immunology (Baltimore, Md. : 1950), vol 203, iss 7 |
| Popis: | Human mesenchymal stem cell (MSC) extracellular vesicles (EV) can reduce the severity of bacterial pneumonia, but little is known about the mechanisms underlying their antimicrobial activity. In the current study, we found that bacterial clearance induced by MSC EV in Escherichia coli pneumonia in C57BL/6 mice was associated with high levels of leukotriene (LT) B4 in the injured alveolus. More importantly, the antimicrobial effect of MSC EV was abrogated by cotreatment with a LTB4 BLT1 antagonist. To determine the role of MSC EV on LT metabolism, we measured the effect of MSC EV on a known ATP-binding cassette transporter, multidrug resistance–associated protein 1 (MRP1), and found that MSC EV suppressed MRP1 mRNA, protein, and pump function in LPS-stimulated Raw264.7 cells in vitro. The synthesis of LTB4 and LTC4 from LTA4 are competitive, and MRP1 is the efflux pump for LTC4. Inhibition of MRP1 will increase LTB4 production. In addition, administration of a nonspecific MRP1 inhibitor (MK-571) reduced LTC4 and subsequently increased LTB4 levels in C57BL/6 mice with acute lung injury, increasing overall antimicrobial activity. We previously found that the biological effects of MSC EV were through the transfer of its content, such as mRNA, microRNA, and proteins, to target cells. In the current study, miR-145 knockdown abolished the effect of MSC EV on the inhibition of MRP1 in vitro and the antimicrobial effect in vivo. In summary, MSC EV suppressed MRP1 activity through transfer of miR-145, thereby resulting in enhanced LTB4 production and antimicrobial activity through LTB4/BLT1 signaling. |
| Databáze: | OpenAIRE |
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