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

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 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.

REDD1/Autophagy Pathway Is Associated with Neutrophil-Driven IL-1β Inflammatory Response in Active Ulcerative Colitis

“…Emerging evidence indicates that NETs expressing active TF are crucially implicated in the pathogenesis of various thromboinflammatory disorders (36,50,51). This study indicates colonic and peripheral blood NETs as a significant source of functional TF in patients with active UC, suggesting mechanisms regarding the observed higher frequency of thrombosis in these patients than in healthy individuals.…”

“…We suggest that blocking IL-1b could be beneficial for active UC (53), as indicated from our findings, the favorable response of anakinra administration in difficult-to-treat UC-associated spondyloarthritis, and the novel anti-inflammatory function of mesalazine/5-ASA through the reduction of IL-1b expression in neutrophils. Inhibition of autophagy-mediated NETosis using known pharmaceutical compounds targeting autophagy machinery at early (IFN-l1/IL-29) (36,54) or late (HCQ) stages (55,56) could also be an alternative therapeutic option in UC.…”

IL-29 promoted obesity-induced inflammation and insulin resistance

“…It is possible that IL-29 might indirectly enhance the migration of monocytes through the MCP-1-CCR2 axis in obesity. Previous studies 49,50 reported that IL-28A had an anti-inflammatory effect by restricting recruitment of IL-1β-expressing neutrophils in arthritis mouse model. In addition, IL-29 exerted an anti-inflammatory function in vitro by inhibiting the formation of neutrophil extracellular traps and the cytoplasmic expression of tissue factor in neutrophils.…”

Insights into IL‐29: Emerging role in inflammatory autoimmune diseases

“…Treatment of IL‐29 inhibited NET formation in neutrophils. Amount of cytoplasmic tissue factors in neutrophil was also hindered after IL‐29 stimulation . In addition, IL‐29 suppressed the neutrophil migratory capacity in prothrombotic and proNETotic functions of neutrophils, indicating the function of IL‐29 in neutrophils, for instance, inhibiting thrombo‐inflammation.…”