Abstract
Early diagnosis of sepsis is crucial since prompt interventions decrease mortality. Citrullinated histone H3 (H3Cit), released from neutrophil extracellular traps (NETs) upon binding of platelets to neutrophils following endotoxin stimulation, has recently been proposed a promising blood biomarker in sepsis. Moreover, microvesicles (MVs), which are released during cell activation and apoptosis and carry a variety of proteins from their parental cells, have also been shown to be elevated in sepsis. In a randomized and placebo-controlled human model of endotoxemia (lipopolysaccharide injection; LPS), we now report significant LPS-induced elevations of circulating H3Cit in 22 healthy individuals. We detected elevations of circulating H3Cit by enzyme-linked immunosorbent assay (ELISA), as well as bound to MVs quantified by flow cytometry. H3Cit-bearing MVs expressed neutrophil and/or platelet surface markers, indicating platelet-neutrophil interactions. In addition, in vitro experiments revealed that H3Cit can bind to phosphatidylserine exposed on platelet derived MVs. Taken together; our results demonstrate that NETs can be detected in peripheral blood during endotoxemia by two distinct H3Cit-specific methods. Furthermore, we propose a previously unrecognized mechanism by which H3Cit may be disseminated throughout the vasculature by the binding to MVs.
Highlights
Despite advances in intensive care, sepsis remains life threatening, with a 20–30% mortality rate[1,2]
Emerging research has demonstrated markers associated with neutrophil extracellular traps (NETs), such as cell free DNA, nucleosomes, and the antimicrobial peptides attached to the NETs upon extrusion in the blood stream of both experimental[15,16,18,19,20,21] and clinical sepsis[9,11,12,13,15,22,23,24,25]
Circulating H3Cit levels are elevated after LPS injection in a human model of endotoxemia
Summary
Despite advances in intensive care, sepsis remains life threatening, with a 20–30% mortality rate[1,2]. Emerging research has demonstrated markers associated with NETs, such as cell free DNA (cfDNA), nucleosomes, and the antimicrobial peptides attached to the NETs upon extrusion in the blood stream of both experimental[15,16,18,19,20,21] and clinical sepsis[9,11,12,13,15,22,23,24,25] These markers are, not NET specific, as they can be elevated in the circulation upon conditions not related to NETosis, such as necrosis, apoptosis[26,27] and neutrophil activation without NET formation[28,29]. The aim of this study was to determine the effect of LPS on circulating H3Cit in a human model of endotoxemia and to investigate a possible presence and cellular origin of H3Cit-bearing MVs
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