Activated platelets present High Mobility Group Box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps

Background: Increasing evidence implicatesboth platelets and neutrophils in the formation, stabilization,and growth of peripheral and coronary thrombi.Neutrophil extracellular traps (NETs) play a key role.The early events in the deregulated cross-talk betweenplatelets and neutrophils are poorly characterized. Objectives:To identify at the molecular level the mechanismthrough which platelets induce the generation of NETs insterile conditions. Patients/Methods: The presence ofNETs was determined in 26 thrombi from patients withacute myocardial infarction by immunohistochemistryand immunofluorescence and markers of NETs assessedin the plasma. In vitro NET generation was studied in staticand in physiological flow conditions. Results: Coronarythrombi mainly consist of activated platelets,neutrophils, and NETs in close proximity of platelets.Activated platelets commit neutrophils to NET generation.The event abates in the presence of competitiveantagonists of the high mobility group box 1 (HMGB1)protein. Hmgb1/platelets fail to elicit NETs, whereasthe HMGB1 alone commits neutrophils to NET generation.Integrity of the HMGB1 receptor, Receptor forAdvanced Glycation End products (RAGE), is requiredfor NET formation, as assessed using pharmacologic andgenetic tools. Exposure to HMGB1 prevents depletion ofmitochondrial potential, induces autophagosome formation,and prolongs neutrophil survival. These metaboliceffects are caused by the activation of autophagy. Blockadeof the autophagic flux reverts platelet HMGB1-elicitedNET generation. Conclusions: Activated platelets presentHMGB1 to neutrophils and commit them to autophagyand NET generation. This chain of events may be responsiblefor some types of thromboinflammatory lesions andindicates novel paths for molecular intervention.