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Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation

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Title: Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation
Authors: O'Dea, K
Tan, YY
Shah, S
Patel, B
Tatham, K
Wilson, M
Soni, S
Takata, M
Item Type: Journal Article
Abstract: Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6Chigh and Ly6Clow monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6Chigh monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6Chigh monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and β3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6Chigh monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6Chigh subset monocytes, become a dominant target cell population for MVs during systemic inflammation, with significant implications for the function and targeting of endogenous and therapeutically administered MVs, lending novel insights into the pathophysiology of pulmonary vascular inflammation.
Issue Date: 5-Jan-2020
Date of Acceptance: 13-Dec-2019
URI: http://hdl.handle.net/10044/1/76410
DOI: 10.1080/20013078.2019.1706708
ISSN: 2001-3078
Publisher: Co-Action Publishing
Start Page: 1
End Page: 16
Journal / Book Title: Journal of Extracellular Vesicles
Volume: 9
Issue: 1
Copyright Statement: © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), whichpermits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Chelsea & Westminster Health Charity
Medical Research Council
Medical Research Council/British Journal of Anaesthesia
Medical Research Council (MRC)
Funder's Grant Number: WSSA_P67555
MR/M018164
MR/M018164/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Extracellular vesicles
microvesicles
monocytes
systemic inflammation
pulmonary vasculature
LUNG-MARGINATED MONOCYTES
IN-VIVO BIODISTRIBUTION
EXTRACELLULAR VESICLES
TISSUE FACTOR
KUPFFER CELLS
BONE-MARROW
MICROPARTICLES
CLEARANCE
EXOSOMES
ACTIVATION
Extracellular vesicles
microvesicles
monocytes
pulmonary vasculature
systemic inflammation
Science & Technology
Life Sciences & Biomedicine
Cell Biology
Extracellular vesicles
microvesicles
monocytes
systemic inflammation
pulmonary vasculature
LUNG-MARGINATED MONOCYTES
IN-VIVO BIODISTRIBUTION
EXTRACELLULAR VESICLES
TISSUE FACTOR
KUPFFER CELLS
BONE-MARROW
MICROPARTICLES
CLEARANCE
EXOSOMES
ACTIVATION
0601 Biochemistry and Cell Biology
Publication Status: Published
Article Number: ARTN 1706708
Online Publication Date: 2020-01-05
Appears in Collections:Department of Surgery and Cancer
Faculty of Medicine