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

Jul 6, 2017The Journal of pathology

Interferon lambda1 and inorganic polyphosphate are new regulators of blood clot inflammation driven by neutrophils

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Abstract

IFN-λ1/IL-29 may hinder NET release and reduce cytoplasmic tissue factor in neutrophils during acute myocardial infarction.

Neutrophils and their released structures, known as neutrophil extracellular traps (NETs), are key players in thromboinflammation.
In an ex vivo model of acute ST-segment elevation myocardial infarction (STEMI), IFN-λ1/IL-29 was shown to suppress NET formation.
Platelet-derived inorganic polyphosphate (polyP) is identified as a trigger for NET induction in the context of STEMI.
PolyP release from activated platelets is influenced by thrombin in the plasma of infarcted arteries.
IFN-λ1/IL-29 treatment counteracts the effects of polyP, leading to decreased NET formation and thromboinflammatory responses.

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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. 3

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

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