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Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1636-1646
Coagulation & its Disorders
miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis
Ana B. Arroyo,1* María P. Fernández-Pérez,1* Alberto del Monte,2* Sonia Águila,1 Raúl Méndez,3 Rebecca Hernández-Antolín,1 Nuria García-Barberá,1 Ascensión M. de los Reyes-García,1 Paula González-Jiménez,3 María I. Arcas,4 Vicente Vicente,1,5 Rosario Menéndez,3,6 Vicente Andrés,2,7 Rocío González- Conejero1# and Constantino Martínez1#
1Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia; 2Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid; 3Servicio de Neumología, Hospital Universitario y Politécnico La Fe/Instituto de Investigación Sanitaria (IIS) La Fe, La Fe; 4Department of Pathology, Hospital Reina Sofía, Murcia; 5CIBER de Enfermedades raras (CIBER-ER), Murcia; 6Centro de Investigación en Red en Enfermedades Respiratorias (CIBER-ES, CB06/06/0028), Madrid and 7CIBER de EnfermedadesCardiovasculares (CIBER-CV), Madrid, Spain.
*ABA, MPF-P, and AdM contributed equally as co-first authors. #RG-C and CM contributed equally as co-senior authors.
ABSTRACT
Neutrophil extracellular traps (NET) induce a procoagulant response linking inflammation and thrombosis. Low levels of miR-146a, a brake of inflammatory response, are involved in higher risk of car- diovascular events, but the mechanisms explaining how miR-146a exerts its function remain largely undefined. The aim of this study was to explore the impact of miR-146a deficiency in NETosis both in sterile and non-ster- ile models in vivo, and to investigate the underlying mechanism. Two mod- els of inflammation were used: (i) Ldlr-/- mice transplanted with bone mar- row from miR-146a-/- or wild-type mice were fed a high-fat diet, generating an atherosclerosis model; and (ii) an acute inflammation model was gen- erated by injecting lipopolysaccharide (1 mg/kg) into miR-146a-/- and wild- type mice. miR-146a deficiency increased NETosis in both models. Accordingly, miR-146a-/- mice showed significantly reduced carotid occlu- sion time and elevated levels of NET in thrombi following FeCl3-induced thrombosis. Infusion of DNAse I abolished arterial thrombosis in both WT and miR-146a-/- mice. Interestingly, miR-146a-deficient mice have aged, hyperreactive and pro-inflammatory neutrophils in their circulation which are more prone to form NET independently of the stimulus. Furthermore, we demonstrated that patients with community-acquired pneumonia with reduced miR-146a levels associated with the T variant of the func- tional rs2431697 had an increased risk of cardiovascular events due, in part, to an increased generation of NET.
Introduction
Neutrophils play a crucial role in immunity and injury repair but also contribute to the development of several thrombo-inflammatory diseases.1 The pathophysio- logical role of neutrophils has become more evident following the discovery of neu- trophil extracellular traps (NET).2 NET are large web-like structures released upon neutrophil activation, comprising a matrix of DNA and histones which are decorat- ed with antimicrobial proteins, such as myeloperoxidase or neutrophil elastase (NE).3 These structures were first identified as a novel innate defense mechanism;3 however, NET also promote thrombosis through activation of platelets and the coagulation cascade.4 Therefore, NET interconnect immunity, inflammation, and thrombosis within a physiological process known as immunothrombosis.5 Thus,
Correspondence:
ROCÍO GONZÁLEZ-CONEJERO
rocio.gonzalez@carm.es, constant@um.es
Received: November 5, 2019. Accepted: June 19, 2020. Pre-published: June 25, 2020.
https://doi.org/10.3324/haematol.2019.240226
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