Inter-α inhibitor protein and its associated glycosaminoglycans protect against histone-induced injury

Chaaban, Hala; Keshari, Ravi S.; Silasi‐Mansat, Robert; Popescu, Narcis I.; Mehta-D’souza, Padmaja; Lim, Yow‐Pin; Lupu, Florea

doi:10.1182/blood-2014-06-582759

Cited by 80 publications

(76 citation statements)

References 62 publications

(95 reference statements)

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“…Not surprisingly, many plasma proteins that neutralize histones are highly negatively charged, such as heparin, 44 pentraxin-3, 45 C-reactive protein, 46 and inter-a inhibitor protein. 21 DNA may also efficiently neutralize the histone charge, and indeed, analogous to nucleosomes, we showed that both ssDNA and dsDNA neutralized the cytotoxicity induced by histones. In support of our results, it was nuclease (5000 U/mL) at 37°C for 1 hour to digest nucleosome DNA before incubation with serum (50%) from 5 healthy donors at 37°C for 1 hour.…”

Section: Discussionmentioning

confidence: 60%

“…Although histone H3 was not degraded in FSAP-deficient serum, some histone neutralization occurred in the absence of FSAP, possibly as a result of histone neutralization by inter-a inhibitor protein or albumin. 20,21 In addition to FSAP, APC has been described to proteolyze histones. 11 In contrast to APC, FSAP becomes activated upon contact with dead cells and histones, supporting a role for FSAP in histone proteolysis in the absence of thrombin formation.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14][15] In addition to immune signaling, histones induce direct cytotoxic effects through physical disturbance of the plasma membrane. 5 Other extracellular effects of histones include antimicrobial effects, 16 particularly when in the form of neutrophil extracellular traps (NETs), 17,18 coagulation activation, 2,[19][20][21][22] and endothelial activation. 23 Histones are highly basic proteins that are strongly conserved throughout evolution and facilitate chromatin compaction by wrapping DNA into a nucleosome complex.…”

Section: Introductionmentioning

confidence: 99%

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DNA and factor VII–activating protease protect against the cytotoxicity of histones

et al. 2017

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Key Points• Free histones, not nucleosomes, are cytotoxic and are degraded by FSAP in serum to protect against cytotoxicity.• Free histone H3 was not detectable in sera of septic baboons and patients with meningococcal sepsis.Circulating histones have been implicated as major mediators of inflammatory disease because of their strong cytotoxic effects. Histones form the protein core of nucleosomes;however, it is unclear whether histones and nucleosomes are equally cytotoxic. Several plasma proteins that neutralize histones are present in plasma. Importantly, factor VII-activating protease (FSAP) is activated upon contact with histones and subsequently proteolyzes histones. We aimed to determine the effect of FSAP on the cytotoxicity of both histones and nucleosomes. Indeed, FSAP protected against histone-induced cytotoxicity of cultured cells in vitro. Upon incubation of serum with histones, endogenous FSAP was activated and degraded histones, which also prevented cytotoxicity. Notably, histones as part of nucleosome complexes were not cytotoxic, whereas DNA digestion restored cytotoxicity. Histones in nucleosomes were inefficiently cleaved by FSAP, which resulted in limited cleavage of histone H3 and removal of the N-terminal tail. The specific isolation of either circulating nucleosomes or free histones from sera of Escherichia coli challenged baboons or patients with meningococcal sepsis revealed that histone H3 was present in the form of nucleosomes, whereas free histone H3 was not detected. All samples showed signs of FSAP activation. Markedly, we observed that all histone H3 in nucleosomes from the patients with sepsis, and most histone H3 from the baboons, was N-terminally truncated, giving rise to a similarly sized protein fragment as through cleavage by FSAP.Taken together, our results suggest that DNA and FSAP jointly limit histone cytotoxicity and that free histone H3 does not circulate in appreciable concentrations in sepsis.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA and factor VII–activating protease protect against the cytotoxicity of histones

et al. 2017

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“…Hence, CRP appears to be an endogenous modulator of the damaging effects of histones. The interalpha inhibitor protein in plasma and its associated glycosaminoglycans was also recently shown to bind to free histones and protect against injurious effects of histones in vitro and in vivo [102]. We have recently found that the host defense lectin, surfactant protein D, also binds to histones and reduces their ability to trigger neutrophil respiratory burst responses [Hoeksema et …”

Section: Platelet Activation and Thrombin Generation By Histonesmentioning

confidence: 99%

Histones as Mediators of Host Defense, Inflammation and Thrombosis

et al. 2016

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Histones are known for their ability to bind to and regulate expression of DNA. However, histones are also present in cytoplasm and extracellular fluids where they serve host defense functions and promote inflammatory responses. Histones are a major component of neutrophil extracellular traps that contribute to bacterial killing but also to inflammatory injury. Histones can act as antimicrobial peptides and directly kill bacteria, fungi, parasites and viruses, in vitro and in a variety of animal hosts. In addition, histones can trigger inflammatory responses in some cases acting through Toll-like receptors or inflammasome pathways. Extracellular histones mediate organ injury (lung, liver), sepsis physiology, thrombocytopenia and thrombin generation and some proteins can bind histones and reduce these potentially harmful effects.

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“…Intravenous infusion of exogenous, full-length glycosaminoglycans (including heparin (a highly-sulfated HS (2, 6)) or the chondroitin sulfate-rich Inter-alpha inhibitor (17)) attenuated histone-induced organ injury. Whether circulating (endothelial glycocalyx-derived) HS fragments would provide similar protective benefit is uncertain, however, particularly given reports that fragmented HS can propagate inflammation via activation of toll-like receptor signaling (18).…”

Section: Discussionmentioning

confidence: 99%

Circulating Heparan Sulfate Fragments Attenuate Histone-Induced Lung Injury Independently of Histone Binding

Zhang

Haeger

Yang

et al. 2017

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Extracellular histones are cationic damage-associated molecular pattern molecules capable of directly inducing cellular injury via charge-mediated interactions with plasma membranes. Accordingly, histones released into the plasma during critical illness are known to contribute to the onset and propagation of lung injury. Vascular injury (with consequent degradation of the endothelial glycocalyx) simultaneously releases anionic heparan sulfate fragments (hexa- to octasaccharides in size) into the plasma. It is unknown whether this endogenous release of heparan sulfate fragments modulates charge-dependent histone cytotoxicity, or if exogenous heparan sulfate fragments could therapeutically attenuate histone-induced lung injury. Using isothermic calorimetry, we found that extracellular histones only bind to heparan sulfate fragments ≥ 10 saccharides in size, suggesting that glycocalyx-derived heparan sulfate hexa/octasaccharides are incapable of intercepting/neutralizing circulating histones. However, we found that even heparan sulfate fragments incapable of histone binding (e.g. tetrasaccharides) attenuated histone-induced lung injury in vivo, suggesting a direct, size-independent protective effect of heparan sulfate. We found that histones had no effect on human neutrophils ex vivo but exerted toll-like receptor-independent cytotoxicity on human pulmonary microvascular endothelial cells in vitro. This cytotoxicity could be prevented by either the addition of negatively-charged (i.e. highly-sulfated) heparan sulfate tetrasaccharides (incapable of binding histones) or decasaccharides (capable of binding histones). Taken together, our findings suggest that heparan sulfate oligosaccharides may directly exert pulmonary endothelial-protective effects that attenuate histone-mediated lung injury.

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Inter-α inhibitor protein and its associated glycosaminoglycans protect against histone-induced injury

Cited by 80 publications

References 62 publications

DNA and factor VII–activating protease protect against the cytotoxicity of histones

DNA and factor VII–activating protease protect against the cytotoxicity of histones

Histones as Mediators of Host Defense, Inflammation and Thrombosis

Circulating Heparan Sulfate Fragments Attenuate Histone-Induced Lung Injury Independently of Histone Binding

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