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Megakaryocytes contain extranuclear histones and may be a source of platelet-associated histones during sepsis.

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.

SUBMITTER: Frydman GH

PROVIDER: S-EPMC7067782 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Megakaryocytes contain extranuclear histones and may be a source of platelet-associated histones during sepsis.

Frydman Galit H GH Tessier Shannon N SN Wong Keith H K KHK Vanderburg Charles R CR Fox James G JG Toner Mehmet M Tompkins Ronald G RG Irimia Daniel D

Scientific reports 20200312 1

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, ...[more]

PMID: 32165642

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Project description:Sepsis is characterized by an intense systemic inflammatory response activating a cascade of proinflammatory events resulting in leukocyte dysregulation and host tissue damage. The lung is particularly susceptible to systemic inflammation, leading to acute lung injury. Key to inflammation-induced lung damage is the excessive migration of neutrophils across the vascular endothelium. The mechanisms which regulate neutrophil activation and migration in sepsis are not well defined but there is growing evidence that platelets are actively involved and play a key role in microvascular permeability and neutrophil-mediated organ damage. We previously identified PKC-delta (PKC?) as a critical regulator of the inflammatory response in sepsis and demonstrated PKC? inhibition was lung protective. However, the role of PKC? in sepsis-induced platelet activation and platelet-leukocyte interactions is not known. In this study, rats underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. Following surgeries, a PKC? inhibitor (200?g/kg) or vehicle (PBS) was administered intra-tracheally. At 24 hours post-surgeries, lung tissue, BAL fluid, and blood samples were collected. While sepsis caused thrombocytopenia, the remaining circulating platelets were activated as demonstrated by increased p-selectin expression, elevated plasma PF4, and enhanced platelet-leukocyte aggregate formation compared to Sham animals. Platelet activation was associated with increased platelet PKC? activity. Inhibition of PKC? attenuated sepsis-induced platelet activation, secretion and aggregate formation. Sepsis-induced thrombocytopenia was also significantly reduced and circulating platelet numbers were similar to sham animals. In the lung, sepsis induced significant influx of platelets and neutrophils and the development of lung injury. Administration of the PKC? inhibitor decreased platelet and neutrophil influx, and was lung protective. Thus, PKC? inhibition modulated platelet activity both locally and systemically, decreased neutrophil influx into the lung, and was lung protective. We demonstrate for the first time that PKC? plays an important role in platelet activation and platelet-neutrophil interaction during sepsis.

Dataset Information

Megakaryocytes contain extranuclear histones and may be a source of platelet-associated histones during sepsis.

Publications

Megakaryocytes contain extranuclear histones and may be a source of platelet-associated histones during sepsis.

Similar Datasets

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