Abstract
Histones are typically located within the intracellular compartment, and more specifically, within the nucleus. When histones are located within the extracellular compartment, they change roles and become damage-associated molecular patterns (DAMPs), promoting inflammation and coagulation. Patients with sepsis have increased levels of extracellular histones, which have been shown to correlate with poor prognosis and the development of sepsis-related sequelae, such as end-organ damage. Until now, neutrophils were assumed to be the primary source of circulating histones during sepsis. In this paper, we show that megakaryocytes contain extranuclear histones and transfer histones to their platelet progeny. Upon examination of isolated platelets from patients with sepsis, we identified that patients with sepsis have increased amounts of platelet-associated histones (PAHs), which appear to be correlated with the type of infection. Taken together, these results suggest that megakaryocytes and platelets may be a source of circulating histones during sepsis and should be further explored.
Highlights
Histones are typically located within the intracellular compartment, and within the nucleus
When histones are outside of the cell, they bind to several different receptors on white blood cells and platelets, such as toll-like receptor 2 and 4 (TLR2 and TLR4)[7,24,25,26]
Extracellular histones are typically degraded by a variety of enzymes, such as histone deacetylases (HDACs); but when they are significantly increased they can bind and activate the surrounding cells and may result in white blood cell activation, platelet activation, and endothelial cell damage[27]
Summary
Histones are typically located within the intracellular compartment, and within the nucleus. Upon examination of isolated platelets from patients with sepsis, we identified that patients with sepsis have increased amounts of platelet-associated histones (PAHs), which appear to be correlated with the type of infection Taken together, these results suggest that megakaryocytes and platelets may be a source of circulating histones during sepsis and should be further explored. Circulating histones can result in activation of nearby platelets and leukocytes, can activate thrombin to exacerbate intravascular clot formation, and can initiate endothelial and epithelial cell death via Toll-like receptor-2 and -4 (TLR2 and TLR4) signaling[4,7,11,12] Both Platelets and megakaryocytes have been shown to express TLR2 and TLR413. We further explore whether platelets from patients with sepsis have significantly higher levels of platelet-associated histones (PAHs)[19]
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