Extracellular histones are major mediators of death in sepsis

By Jun Xu, Xiaomei Zhang, Rosana Pelayo, M. Monestier, C. Ammollo, F. Semeraro, F. Taylor, N. Esmon, F. Lupu, C. Esmon. Nature Medicine, 2009

1,509 citations recorded by the source corpus.

Hyperinflammatory responses can lead to a variety of diseases, including sepsis. We now report that extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis. They can be targeted pharmacologically by antibody to histone or by activated protein C (APC). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor (TNF) or cecal ligation and puncture models of sepsis. Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo, histone administration resulted in neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage and macro- and microvascular thrombosis. We detected histone in the circulation of baboons challenged with Escherichia coli, and the increase in histone levels was accompanied by the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co-infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality, which was reversed by treatment with antibody to histone. We conclude that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases.

Subfields: Immunology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/0a3ac2a129491af9f252d24a41e1e923eb86a09c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. P. Kubes
2. Arturo Zychlinsky
3. V. Brinkmann
4. V. Papayannopoulos
5. K. Martinod
6. Guido Kroemer
7. D. Wagner
8. B. Yipp

In Public Health, Environmental and Occupational Health

1. Guido Kroemer
2. L. Galluzzi
3. V. Papayannopoulos
4. Arturo Zychlinsky
5. Kathleen D. Metzler

Citations in the corpus

• NETosis: how vital is it? (2013, background): “In addition, it was found that protein C, a physiological anticoagulant, specifically cleaved extracellular histones from NETs, thereby reducing their toxic vascular effects.(93) Currently, researchers are defining how NETs promote thrombosis(96,97) and developing new concepts such as immunothrombos”
• Neutrophil extracellular traps: Is immunity the second function of chromatin? (2012, background): “, 2012) showed that histones also kill mammalian cells, and implicated this toxicity in the pathogenesis of sepsis (Xu et al., 2009).”
• The Pathogenesis of Sepsis (2011, background): “The protein C pathway members also have cytoprotective functions (77), which is surely beneficial during the cellular destruction of sepsis (see the Apoptosis and Necrosis section, above), as was most recently demonstrated by the ability of activated protein C to degrade cytotoxic histones released ”
• Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis (2012, background): “This latter effect has also been observed in mice after an injection of large quantities of histones, leading to sepsis-like disease (34).”
• Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps (2010, background): “Interestingly, although histone degradation fragments are more potent antimicrobials than the intact proteins (Kawasaki and Iwamuro, 2008), the degradation of histones reduces cytotoxicity against the host during sepsis (Xu et al., 2009).”
• Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones (2012, methodology): “These data together with the previous studies [45] confirms the cytotoxic capability of histones on the host cells.”
• Molecular mechanisms of necroptosis: an ordered cellular explosion (2010, background): “Histones released from necrotic cells have a major pathogenic role in sepsis, and their neutralization by antibodies or activated protein C can prevent organismal lethalit”
• Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. (2012, background): “Esmon and colleagues recently reported that histones are directly cytopathic to endothelial cells in vitro and that immunoneutralization of histones in vivo reduced organ damage and enhanced survival in animal models of sepsis and endotoxemia (Xu et al., 2009).”
• Thrombosis: tangled up in NETs. (2014, methodology): “Reproduced from Xu et al with permission.(30) BLOOD, 1 MAY 2014 x VOLUME 123, NUMBER 18 DNA NETs IN THROMBOSIS 2769 For personal use only.”
• Microglial cell origin and phenotypes in health and disease (2011, background): “Such danger signals are induced by metabolic products (for example, oxidized low-density lipoprotein (LDL)) and molecules released by dead cells (for example, high-mobility group box 1 (HMGB1) and nucleotides”