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

bioRxiv

Authors: Gomez, Ingrid; Ward, Ben; Souilhol, Celine; Recarti, Chiara; Ariaans, Mark; Johnston, Jessica; Burnett, Amanda; Mahmoud, Marwa; Luong, Le Anh; West, Laura;
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Publisher: Cold Spring Harbor Laboratory

Abstract

Neutrophils have been implicated in the pathogenesis of atherosclerosis, a lipid-driven disease of arteries, but they are seldom found in atherosclerotic plaques. To resolve this longstanding paradox, we investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Clinical and pre-clinical studies revealed that levels of circulating neutrophil microvesicles were enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulated at disease-prone regions of arteries that are exposed to complex flow patterns, and they promoted vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, it was demonstrated that neutrophil microvesicles promoted inflammatory gene expression by delivering a microRNA (miR-155) that enhanced NF-B activation. Similary, neutrophil microvesicles increased miR-155 and enhanced NF-B at disease-prone sites of disturbed flow in arteries of mice. We conclude that delivery of microvesicles carrying miR-155 to disease-prone regions of arteries provides a novel mechanism by which neutrophils contribute to vascular inflammation and atherogenesis.