Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis.

ΤίτλοςAutophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis.
Publication TypeJournal Article
Year of Publication2012
AuthorsKambas K, Mitroulis I, Apostolidou E, Girod A, Chrysanthopoulou A, Pneumatikos I, Skendros P, Kourtzelis I, Koffa M, Kotsianidis I, Ritis K
JournalPloS one
Volume7
Issue9
Paginatione45427
Date Published2012
ISSN1932-6203
Λέξεις κλειδιάAutophagy, Cells, Cultured, Humans, Macrolides, Neutrophils, Phosphatidylinositol 3-Kinase, Protein Transport, Sepsis, Thromboplastin
Abstract

BACKGROUND: Sepsis is associated with systemic inflammatory responses and induction of coagulation system. Neutrophil extracellular traps (NETs) constitute an antimicrobial mechanism, recently implicated in thrombosis via platelet entrapment and aggregation. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrate for the first time the localization of thrombogenic tissue factor (TF) in NETs released by neutrophils derived from patients with gram-negative sepsis and normal neutrophils treated with either serum from septic patients or inflammatory mediators involved in the pathogenesis of sepsis. Localization of TF in acidified autophagosomes was observed during this process, as indicated by positive LC3B and LysoTracker staining. Moreover, phosphatidylinositol 3-kinase inhibition with 3-MA or inhibition of endosomal acidification with bafilomycin A1 hindered the release of TF-bearing NETs. TF present in NETs induced thrombin generation in culture supernatants, which further resulted in protease activated receptor-1 signaling. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the involvement of autophagic machinery in the extracellular delivery of TF in NETs and the subsequent activation of coagulation cascade, providing evidence for the implication of this process in coagulopathy and inflammatory response in sepsis.

DOI10.1371/journal.pone.0045427
Alternate JournalPLoS ONE