Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium
Ingrid Gomez, Ben Ward, Céline Souilhol, Chiara Recarti, Mark P. Ariaans, Jessica Johnston, Amanda Burnett, Marwa Mahmoud, Le Anh Luong, Laura West, Merete Long, Siôn Parry, Rachel Woods, Carl J. Hulston, Birke J. Benedikter, Chiara Niespolo, Rohit Bazaz, Sheila Francis, Endre Kiss‐Toth, Marc van Zandvoort, Andreas Schober, Paul G. Hellewell, Paul C. Evans, Victoria Ridger
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.