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

• Type of Material: Article
• Authors: Ingrid Gomez, University of Sheffield; Ben Ward, University of Sheffield; Celine Souilhol, University of Sheffield; Chiara Recarti, University of Sheffield; Mark Ariaans, University of Sheffield; Jessica Johnston, University of Sheffield; Amanda Burnett, University of Sheffield; Marwa Mahmoud, Emory University; Le Anh Luong, Queen Mary University, London; Laura West, University of Sheffield; Merete Long, University of Sheffield; Sion Parry, Loughborough University; Rachel Woods, Loughborough University; Carl Hulston, Loughborough University; Birke Benedikter, Maastricht University; Chiara Niespolo, University of Sheffield; Rohit Bazaz, University of Sheffield; Sheila Francis, University of Sheffield; Endre Kiss-Toth, University of Sheffield; Marc van Zandvoort, Maastricht University; Andreas Schober, Ludwig-Maximilian University of Munich; Paul Hellewell, University of Sheffield; Paul C Evans, University of Sheffield; Victoria Ridger, University of Sheffield
• Language: English
• Date: 2020-01-10
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-019-14043-y
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Grant/Funding Information: This work was funded by: British Heart Foundation Programme Grant (CS, PE); British Heart Foundation Project Grants PG/09/067/27901 (AB, VR), PG/13/55/30365 (LW, SF), PG/14/38/30862 (CR, VR), PG/16/44/32146 (JJ, EKT, SF); British Heart Foundation Studentship FS/14/8/30605 (BW, VR); MRC Fellowship MR/K023977/1 (RB); and European Union’s Horizon 2020 Marie Skłodowska-Curie Innovative Training Network, TRAIN 721532 (CN).
• Keywords: miRNAs; Atherosclerosis; Lymphocytes
• Research Categories: Health Sciences, Medicine and Surgery

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.