Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/13378
miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis.
Arroyo, Ana B | Fernandez-Perez, Maria P | del Monte, Alberto CNIC | Aguila, Sonia | Mendez, Raul | Hernandez-Antolin, Rebecca | Garcia-Barber, Nuria | de Los Reyes-Garcia, Ascension M | Gonzalez-Jimenez, Paula | Arcas, Maria I | Vicente, Vicente | Menendez, Rosario | Andres, Vicente CNIC | Gonzalez-Conejero, Rocio | Martinez, Constantino
Haematologica. 2021; 106(6):1636-1646
Neutrophil extracellular traps (NETs) induce a procoagulant response linking inflammation and thrombosis. Low levels of miR-146a, a brake of inflammatory response, are involved in higher risk for cardiovascular 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-sterile models in vivo, and to inquire into the underlying mechanism. Two models of inflammation were performed: 1) Ldlr-/- mice transplanted with bone marrow from miR-146a-/- or wild type (WT) were fed high-fat diet, generating an atherosclerosis model; and 2) an acute inflammation model was generated by injecting lipopolysaccharide (LPS) (1 mg/Kg) into miR-146a-/- and WT mice. miR-146a deficiency increased NETosis in both models. Accordingly, miR-146a-/- mice showed significant reduced carotid occlusion time and elevated levels of NETs in thrombi following FeCl3-induced thrombosis. Infusion of DNAse I abolished arterial thrombosis in WT and miR-146a-/- mice. Interestingly, miR-146a deficient mice have aged, hyperreactive and pro-inflammatory neutrophils in circulation that are more prone to form NETs independently of the stimulus. Furthermore, we demonstrated that community acquired pneumonia (CAP) patients with reduced miR-146a levels associated with the T variant of the functional rs2431697, presented an increased risk for cardiovascular events due in part to an increased generation of NETs.
Extracellular Traps | MicroRNAs | Thrombosis | Aged | Animals | Humans | Mice | Mice, Knockout | Neutrophils
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