Extracellular Histone H3 Induces Pyroptosis During Sepsis and May Act Through NOD2 and VSIG4/NLRP3 Pathways

Shi, Chunxia; Wang, Yao; Chen, Qian; Jiao, Fangzhou; Pei, Maohua; Gong, Zhengliang

doi:10.3389/fcimb.2020.00196

Cited by 43 publications

(34 citation statements)

References 35 publications

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“…High levels of histone H3 were found in LPS-immersed ANA-1 macrophages. The mRNA and protein levels of NOD2, caspase-1, gasdermin D, IL-1β, IL-18 were increased in LPS-stimulated group, which could be reversed by H3 antibodies ( 43 ). NLRP3, a downstream factor of NOD2, ran in parallel with NOD2 level and eventually led to pyroptosis ( 43 ).…”

Section: Immunopathological Role Of Circulating Histones In Sepsismentioning

confidence: 99%

“…The mRNA and protein levels of NOD2, caspase-1, gasdermin D, IL-1β, IL-18 were increased in LPS-stimulated group, which could be reversed by H3 antibodies ( 43 ). NLRP3, a downstream factor of NOD2, ran in parallel with NOD2 level and eventually led to pyroptosis ( 43 ). Of note, extracellular histones released after pyroptosis have been regarded as one important contributor of serum CHs ( 11 ).…”

Section: Immunopathological Role Of Circulating Histones In Sepsismentioning

confidence: 99%

“…Nucleotide-binding oligomerization domain 2 (NOD2), a member of NOD like receptor family, is involved in histone-originated inflammatory procedures as well ( 43 ). High levels of histone H3 were found in LPS-immersed ANA-1 macrophages.…”

Section: Immunopathological Role Of Circulating Histones In Sepsismentioning

confidence: 99%

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Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

Wan

Luo

et al. 2021

Front. Immunol.

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Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and is associated with high morbidity and mortality. Circulating histones (CHs), a group of damage-associated molecular pattern molecules mainly derived from neutrophil extracellular traps, play a crucial role in sepsis by mediating inflammation response, organ injury and death through Toll-like receptors or inflammasome pathways. Herein, we first elucidate the molecular mechanisms of histone-induced inflammation amplification, endothelium injury and cascade coagulation activation, and discuss the close correlation between elevated level of CHs and disease severity as well as mortality in patients with sepsis. Furthermore, current state-of-the-art on anti-histone therapy with antibodies, histone-binding proteins (namely recombinant thrombomodulin and activated protein C), and heparin is summarized to propose promising approaches for sepsis treatment.

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Section: Immunopathological Role Of Circulating Histones In Sepsismentioning

confidence: 99%

Section: Immunopathological Role Of Circulating Histones In Sepsismentioning

confidence: 99%

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Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

Wan

Luo

et al. 2021

Front. Immunol.

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“…In particular, NET-derived histones account for ~70% of NET-associated proteins (16) and have been associated with endothelial damage and multiple organ dysfunction in acute states such as sepsis (17), acute pancreatitis (18), acute respiratory distress syndrome (19), and severe trauma (20). High levels of circulating histones (up to 250 μg/ml after trauma) (20) activate and damage endothelial cells via pore formation (21,22), engagement of innate sensors such as Toll-like receptors (23)(24)(25) and the NLRP3 inflammasome (26,27), and forced release of von Willebrand factor (vWF) (28). On balance, the result is a hypercoagulable state and an increased risk of vascular events including thrombosis.…”

Section: Introductionmentioning

confidence: 99%

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

Shi¹,

Gandhi²,

Smith³

et al. 2021

JCI Insight

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Neutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap/NET-derived histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the FDA-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET-and histone-accelerated disease states.

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Section: Introductionmentioning

confidence: 99%

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

Shi

Gandhi

Smith

et al. 2021

Preprint

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Neutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap/NET-derived histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the FDA-approved polyanionic agent defibrotide (a pleotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and cell death, whether triggered by purified NETs, COVID-19 serum containing high levels of NETs, or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.

show abstract

Extracellular Histone H3 Induces Pyroptosis During Sepsis and May Act Through NOD2 and VSIG4/NLRP3 Pathways

Cited by 43 publications

References 35 publications

Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

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