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Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps
Author(s) -
Maugeri N.,
Campana L.,
Gavina M.,
Covino C.,
De Metrio M.,
Panciroli C.,
Maiuri L.,
Maseri A.,
D'Angelo A.,
Bianchi M. E.,
RovereQuerini P.,
Manfredi A. A.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12710
Subject(s) - neutrophil extracellular traps , hmgb1 , platelet , autophagy , platelet activation , microbiology and biotechnology , chemistry , receptor , extracellular , biology , immunology , inflammation , apoptosis , biochemistry
Summary Background Increasing evidence implicates both platelets and neutrophils in the formation, stabilization, and growth of peripheral and coronary thrombi. Neutrophil extracellular traps ( NET s) play a key role. The early events in the deregulated cross‐talk between platelets and neutrophils are poorly characterized. Objectives To identify at the molecular level the mechanism through which platelets induce the generation of NET s in sterile conditions. Patients/Methods The presence of NET s was determined in 26 thrombi from patients with acute myocardial infarction by immunohistochemistry and immunofluorescence and markers of NET s assessed in the plasma. In vitro NET generation was studied in static and in physiological flow conditions. Results Coronary thrombi mainly consist of activated platelets, neutrophils, and NET s in close proximity of platelets. Activated platelets commit neutrophils to NET generation. The event abates in the presence of competitive antagonists of the high mobility group box 1 ( HMGB 1) protein. Hmgb1 −/− platelets fail to elicit NET s, whereas the HMGB 1 alone commits neutrophils to NET generation. Integrity of the HMGB 1 receptor, Receptor for Advanced Glycation End products (RAGE), is required for NET formation, as assessed using pharmacologic and genetic tools. Exposure to HMGB 1 prevents depletion of mitochondrial potential, induces autophagosome formation, and prolongs neutrophil survival. These metabolic effects are caused by the activation of autophagy. Blockade of the autophagic flux reverts platelet HMGB 1‐elicited NET generation. Conclusions Activated platelets present HMGB 1 to neutrophils and commit them to autophagy and NET generation. This chain of events may be responsible for some types of thromboinflammatory lesions and indicates novel paths for molecular intervention.