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J Pathol. 2017 Sep;243(1):111-122. doi: 10.1002/path.4935. Epub 2017 Aug 7.

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

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Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Cardiology Department, Democritus University of Thrace, Alexandroupolis, Greece.
Department of Clinical Pathobiochemistry, and Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universitat Dresden, Dresden, Germany.
Natural Products Synthesis and Bioorganic Chemistry Laboratory, Institute of Nanoscience and Nanotechnology, NCSR 'Demokritos', Greece.
Center for Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany.
Department of Pathology, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.
Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Athens, Greece.
First Department of Internal Medicine, University General Hospital of Alexandroupolis, Democritus University Thrace, Alexandroupolis, Greece.
Chemical Laboratories, Agricultural University of Athens, Athens, Greece.
Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.


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 FeCl3 -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.


acute coronary syndrome; autophagy; inorganic polyphosphate; interferon lambda; neutrophil extracellular traps

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