Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps

Abstract

Summary Background Increasing evidence implicates both 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 between platelets and neutrophils are poorly characterized. Objectives To identify at the molecular level the mechanism through which platelets induce the generation of NETs in sterile conditions. Patients/Methods The presence of NETs was determined in 26 thrombi from patients with acute myocardial infarction by immunohistochemistry and immunofluorescence and markers of NETs 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 NETs 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 (HMGB1) protein. Hmgb1−/− platelets fail to elicit NETs, whereas the HMGB1 alone commits neutrophils to NET generation. Integrity of the HMGB1 receptor, Receptor for Advanced Glycation End products (RAGE), is required for NET formation, as assessed using pharmacologic and genetic tools. Exposure to HMGB1 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 HMGB1‐elicited NET generation. Conclusions Activated platelets present HMGB1 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.

Cell death, clearance and immunity in the skeletal muscle

“…45 Apoptosis has been described in inflammatory myopathies, 46,47 at least in some cases as a result of the cytotoxic action of T lymphocytes. Finally, the generation of neutrophil extracellular traps (NETs), an event strictly associated with the activation of autophagy pathway in inflammatory leukocytes 48 and modulated by the recognition of apoptotic cells, 49 has been described in the muscle upon ischemia-reperfusion injury. 50 Further studies will evaluate the relevance of NET contribution to muscle remodeling during autoimmune diseases and in homeostatic conditions.…”

Role for Neutrophil Extracellular Traps (NETs) and Platelet Aggregation in Early Sepsis-induced Hepatic Dysfunction

“…been thought that extracellular HMGB1 is a late mediator of sepsis (29); however, it is also upregulated by activated platelets in the early phase of sepsis (30). HMGB1 acts as an early and late mediator of septic lethality.…”

High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule

“…HMGB1 has two nuclear localization sequences (NLSs) located in box A (aa [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] and between box B and the C tail (aa 179-185). Truncated mutants of HMGB1 identified that HMGB1 box B protein preserves the cytokine activity of HMGB1 (21), whereas recombinant box A protein acts as an antagonist of HMGB1 (22).…”