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

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

Abstract

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.

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

MeSH terms

  • Animals
  • Autophagy
  • Blood Coagulation*
  • Blood Platelets / metabolism*
  • Case-Control Studies
  • Chlorides
  • Disease Models, Animal
  • Extracellular Traps / metabolism
  • Ferric Compounds
  • Humans
  • Inflammation / blood*
  • Inflammation / chemically induced
  • Inflammation / prevention & control
  • Interferons
  • Interleukins / administration & dosage
  • Interleukins / blood*
  • Male
  • Mice, Inbred C57BL
  • Neutrophils / metabolism*
  • Platelet Activation
  • Polyphosphates / blood*
  • ST Elevation Myocardial Infarction / blood*
  • ST Elevation Myocardial Infarction / diagnostic imaging
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Thrombin / metabolism
  • Thrombosis / blood*
  • Thrombosis / chemically induced
  • Thrombosis / prevention & control

Substances

  • Chlorides
  • Ferric Compounds
  • IFNL1 protein, human
  • IL28A protein, mouse
  • Interleukins
  • Polyphosphates
  • Interferons
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Thrombin
  • ferric chloride