Resolving Thromboinflammation in the Brain After Ischemic Stroke?

Kehrel, Beate E.; Fender, Anke C.

doi:10.1161/circulationaha.116.022858

Cited by 17 publications

(18 citation statements)

References 18 publications

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“…It is suggested that platelet‐derived polyP is linked to immunothrombosis mainly through interactions with several steps of the coagulation cascade . However, its role in the interplay between platelets and immune cells, in the context of thromboinflammation and NETs, remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Interferon lambda1/IL‐29 and inorganic polyphosphate are novel regulators of neutrophil‐driven thromboinflammation

Chrysanthopoulou

Kambas

Stakos

et al. 2017

The Journal of Pathology

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Neutrophils and neutrophil-released meshwork structures termed neutrophil extracellular traps (NETs) are major mediators of thromboinflammation and emerging targets for therapy, yet the mechanisms and pathways that control the role of neutrophils in thromboinflammation remain poorly understood. Here, we explored the role of IFN-λ1/IL-29, a major antiviral cytokine recently shown to suppress the neutrophil migratory capacity, in prothrombotic and proNETotic functions of neutrophils. In an ex vivo human experimental setting of acute ST-segment elevation myocardial infarction (STEMI), we show that IFN-λ1/IL-29 hinders NET release and diminishes the amount of cytoplasmic TF in neutrophils. Since platelet-neutrophil interaction plays a major role in NET-induced thromboinflammation, we further studied how IFN-λ1/IL-29 may interrupt this interaction. In this context, we identified inorganic polyphosphate (polyP) as a platelet-derived NET inducer in STEMI. In arterial STEMI thrombi, polyP was present in platelets and in close proximity to NET remnants. PolyP release from activated platelets was dependent on thrombin present in infarcted artery plasma, resulting in NET formation by promoting mTOR inhibition and autophagy induction. The effect of polyP on mTOR inhibition was counteracted by IFN-λ1/IL-29 treatment, leading to inhibition of NET formation. Consistently, we show in an in vivo model of FeCl -induced arterial thrombosis that IFN-λ2/IL-28A exerts strong antithrombotic potential. Taken together, these findings reveal a novel function of IFN-λ1/IL-29 in the suppression of thromboinflammation. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 99%

Interferon lambda1/IL‐29 and inorganic polyphosphate are novel regulators of neutrophil‐driven thromboinflammation

Chrysanthopoulou

Kambas

Stakos

et al. 2017

The Journal of Pathology

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“…Furthermore, the stroke burden continues to increase, especially in developing countries such as China [1, 2]. Ischemic stroke (IS) is a major type of stroke defined as a cerebrovascular accident caused by occlusion of the cerebral arteries leading to sudden neurologic deficit, such as loss of motor function, altered sensations, and cognition or language impairments [3].…”

Section: Introductionmentioning

confidence: 99%

Tagging Functional Polymorphism in 3’ Untranslated Region of Methylene Tetrahydrofolate Reductase and Risk of Ischemic Stroke

Shi¹,

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The association between genetic polymorphisms in the exon or untranslated region of the methylenetetrahydrofolate reductase gene (MTHFR) and the risk of human ischemic stroke (IS) has been well-documented. In this study, we focused on a polymorphism previously screened by high-throughput analysis and on its potential function in patients with IS Methods: This hospital-based case-control study was conducted in 400 patients and 400 healthy volunteers. Genotyping was conducted using TaqMan probes. Potential interactions were predicted by multiple bioinformatics analysis. Relative expression levels of MTHFR were detected confirmed by dual-luciferase assay. Results: The MTHFR polymorphism rs142884651 was significantly associated with a decreased risk of IS compared with the wild-type GA genotype (P = 0.02) and AA genotype (P = 0.001). According to bioinformatics analysis and luciferase assay, this polymorphism could attenuate the binding of let-7f and miR-196a (P = 0.021 and 0.019, respectively) leading to the accumulation of MTHFR and degradation of serum homocysteine, and resulting in a better IS outcome. Conclusion: This study demonstrated that the MTHFR rs142884651 polymorphism is associated with a decreased risk of IS and may act as a biomarker of short-term outcome in patients with IS.

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“…While there are distinct mechanisms by which both inflammation and thrombosis can lead to deleterious events after SAH, both of these pathological events have cross talk by which they potentiate each other ( 30 ). The overlap between inflammation and thrombosis, called thromboinflammation, has been reported to play roles in a number of brain diseases/damage, including ischemia ( 31 – 34 ). Since ischemia also plays a role in patient outcome as a downstream deleterious event from SAH, thromboinflammation may be an overlooked pathophysiology after SAH.…”

Section: Sah Pathophysiologymentioning

confidence: 99%

“…In most pathologies, including SAH, both pro- and anti-inflammatory pathways are activated to promote debris/toxin clearance and repair of injured tissue, respectively. Since pro-inflammatory cytokines and downstream signaling is linked with thromboinflammation ( 34 ), it is critical to pursue agents which mitigate pro-inflammatory cytokines. So far research has largely focused on this, however, anti-inflammatory signaling aids in repair and healing, thus this arm of inflammation should remain active (or upregulated) after reducing thromboinflammation.…”

Section: Thromboinflammation As a Therapeutic Target To Prevent DCImentioning

confidence: 99%

The Role of Thromboinflammation in Delayed Cerebral Ischemia after Subarachnoid Hemorrhage

et al. 2017

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Delayed cerebral ischemia (DCI) is a major determinant of patient outcome following aneurysmal subarachnoid hemorrhage. Although the exact mechanisms leading to DCI are not fully known, inflammation, cerebral vasospasm, and microthrombi may all function together to mediate the onset of DCI. Indeed, inflammation is tightly linked with activation of coagulation and microthrombi formation. Thromboinflammation is the intersection at which inflammation and thrombosis regulate one another in a feedforward manner, potentiating the formation of thrombi and pro-inflammatory signaling. In this review, we will explore the role(s) of inflammation and microthrombi in subarachnoid hemorrhage (SAH) pathophysiology and DCI, and discuss the potential of targeting thromboinflammation to prevent DCI after SAH.

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Resolving Thromboinflammation in the Brain After Ischemic Stroke?

Cited by 17 publications

References 18 publications

Interferon lambda1/IL‐29 and inorganic polyphosphate are novel regulators of neutrophil‐driven thromboinflammation

Interferon lambda1/IL‐29 and inorganic polyphosphate are novel regulators of neutrophil‐driven thromboinflammation

Tagging Functional Polymorphism in 3’ Untranslated Region of Methylene Tetrahydrofolate Reductase and Risk of Ischemic Stroke

The Role of Thromboinflammation in Delayed Cerebral Ischemia after Subarachnoid Hemorrhage

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