Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium

Abstract

Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions.

Metadata

Item Type:	Article
Authors/Creators:	Gomez, I. Ward, B. Souilhol, C. Recarti, C. Ariaans, M. https://orcid.org/0000-0002-7392-8278 Johnston, J. Burnett, A. Mahmoud, M. Luong, L.A. West, L. Long, M. Parry, S. Woods, R. Hulston, C. Benedikter, B. Niespolo, C. Bazaz, R. Francis, S. https://orcid.org/0000-0001-6552-0339 Kiss-Toth, E. https://orcid.org/0000-0003-4406-4017 van Zandvoort, M. Schober, A. Hellewell, P. Evans, P.C. Ridger, V. https://orcid.org/0000-0003-4163-669X
Copyright, Publisher and Additional Information:	© 2019 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 11 December 2019 Published: 10 January 2020
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Funding Information:	Funder Grant number BRITISH HEART FOUNDATION PG/14/38/30862 British Heart Foundation BHF-PG/14/38/30862 British Heart Foundation BHF-FS/14/8/30605
Depositing User:	Symplectic Sheffield
Date Deposited:	20 Jan 2020 13:59
Last Modified:	20 Jan 2020 14:07
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41467-019-14043-y
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:155777

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Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium

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