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Natural killer cells induce neutrophil extracellular trap formation in venous thrombosis

Published on Feb 1, 2019in Journal of Thrombosis and Haemostasis4.662
· DOI :10.1111/jth.14339
Francois-Rene Bertin9
Estimated H-index: 9
(UQ: University of Queensland),
Ryan N. Rys3
Estimated H-index: 3
+ 3 AuthorsMark Blostein21
Estimated H-index: 21
(McGill University)
Abstract
Essentials Neutrophil extracellular traps (NETs) are generated during deep vein thrombosis (DVT). The role of interferon γ (IFNγ) and natural killer (NK) cells in NET formation was studied. IFNγ promote venous thrombosis through NET formation. NK cell depletion reduces DVT. SUMMARY: Background Neutrophils contribute to venous thrombosis through the release of neutrophil extracellular traps (NETs), but the mechanism triggering their formation remains unclear. In vitro data show that interferon (IFN)-γ induces the formation of NETs. Objectives To determine whether IFN-γ and the transcription factor T-box expressed on T cells (Tbet) promote venous thrombosis through neutrophil activation. Methods Venous thrombosis was induced by flow restriction in the inferior vena cava in IFN-γ , Tbet or wild-type (WT) mice. After 48 h, thrombus size was measured by the use of high-frequency ultrasound. NET formation was determined by immunofluorescence. Results and Conclusions Thrombus formation was reduced in Tbet and IFN-γ mice, suggesting that Tbet/IFN-γ-expressing cells are required for venous thrombosis. The number of NETs formed during thrombosis was significantly lower in Tbet and IFN-γ mice. NET formation was also decreased in WT mice treated with an IFN-γ-blocking antibody. Injection of recombinant IFN-γ into IFN-γ mice rescued the phenotype. Natural killer (NK) cells were specifically depleted prior to venous thrombosis induction. NK cell depletion results in decreased NET formation and smaller thrombi, suggesting that NK cells are required for thrombus development. In depleted mice, adoptive transfer of WT NK cells induced a similar thrombosis burden as in WT mice. In contrast, adoptive transfer of IFN-γ NK cells resulted in thrombi similar in size to those in depleted mice. In vitro, we showed that WT neutrophils released fewer NETs when they were cocultured with IFN-γ NK cells. This study demonstrates that NK cell-dependent IFN-γ production is crucial for thrombus development by promoting the formation of NETs by neutrophils.
  • References (34)
  • Citations (3)
References34
Newest
#1Geert-Jan Geersing (UU: Utrecht University)H-Index: 10
#2Selma Cazemier (UU: Utrecht University)H-Index: 1
Last. Arno W. Hoes (UU: Utrecht University)H-Index: 83
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Objectives Recent studies in referred populations of patients with superficial venous thrombosis (SVT) report risks of venous thromboembolic (VTE) sequelae (deep vein thrombosis or pulmonary embolism) as high as 25%. Likely, these estimates are lower in non-referred patients, but large-scale population-based studies are lacking. We aimed to estimate the incidence rate of SVT in primary care and quantify its risk of VTE sequelae. Design A retrospective cohort study, using International Classifica...
3 CitationsSource
#1Lisa-Marie Mauracher (Medical University of Vienna)H-Index: 3
#2Florian Posch (Medical University of Vienna)H-Index: 16
Last. Johannes Thaler (Medical University of Vienna)H-Index: 21
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: Essentials Neutrophil extracellular traps (NETs) might play a role in cancer-related coagulopathy. We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE). We found a constant association with VTE for citrullinated histone H3. Biomarkers of NET formation could reflect a novel pathomechanism of cancer-related VTE. SUMMARY: Background Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of canc...
22 CitationsSource
#1Tanja SchönfelderH-Index: 10
#2Moritz BrandtH-Index: 13
Last. Philip WenzelH-Index: 43
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The role of leukocytes in deep vein thrombosis (DVT) resolution is incompletely understood. We determined how depletion of lysozyme positive (LysM+) cells and a switched-off type 1 immune response influences thrombus resolution. DVT was induced in 12-week-old male mice by inferior vena cava (IVC) stenosis. Toxin mediated depletion of myeloid cells improved thrombus resolution in mice with Cre-inducible expression of the diphtheria toxin receptor in LysM+ cells. This correlated with decreased CD4...
7 CitationsSource
#1Lai Heng Lee (NUS: National University of Singapore)H-Index: 1
#2Alexander Gallus (Flinders University)H-Index: 48
Last. Chau-Chung Wu (NTU: National Taiwan University)H-Index: 1
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Introduction Despite a marked recent increase in the number of publications describing the incidence of venous thromboembolism (VTE) in Asia, and especially in mainland China, Hong Kong, Taiwan, Korea, Japan and Singapore, there remains a lack of consensus on the true risks, and trends over time, to inform appropriate clinical practice. The purpose of this systematic review was therefore to examine evidence about the incidence of symptomatic VTE in Asia. Methods Databases were searched for studi...
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Objective—Coagulation and inflammation are inter-related. Gas6 (growth arrest–specific 6) promotes venous thrombosis and participates to inflammation through endothelial-innate immune cell interact...
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Kubes and Fassl discuss the role of NETosis in sterile inflammation and disease, and propose windows of opportunity for therapeutic targeting of NETs.
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Objectives— Coagulation and inflammation are inter-related. Gas6 (growth arrest–specific 6) promotes venous thrombosis and participates to inflammation through endothelial-innate immune cell interactions. Innate immune cells can provide the initiating stimulus for venous thrombus development. We hypothesize that Gas6 promotes monocyte recruitment during venous thrombosis. Approach and Results— Deep venous thrombosis was induced in wild-type and Gas6-deficient (−/−) mice using 5% FeCl3 and flow r...
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#1Natascha Luther (University of Mainz)H-Index: 2
#2Fatemeh Shahneh (University of Mainz)H-Index: 2
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Rationale:Immune cells play an important role during the generation and resolution of thrombosis. T cells are powerful regulators of immune and nonimmune cell function, however, their role in steri...
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#1Irene Bonaccorsi (UNIME: University of Messina)H-Index: 16
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Abstract Natural killer (NK) cells are innate lymphocytes which have recently been proposed to play an immunoregulatory role in the pathogenesis and progression of atherosclerosis. Although several studies have evaluated the frequency and the functions of NK cells both in human and in experimental animal models of atherosclerosis, it is yet not clear whether NK cells might behave as protective or pro-atherogenic effectors. Here, we review current knowledge regarding the role of NK cells in ather...
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#2Catherine A. Lemarié (McGill University)H-Index: 16
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Venous thromboembolism (VTE) is the most common morbid complication related to cancer and its treatments. Although malignancies are characterized by a hypercoagulable state leading to VTE, the pathophysiology of this state has not been well studied. Growth arrest specific 6 (Gas6) is a protein that has pro-coagulant properties. Gas6 deficient mice develop smaller venous thrombi as compared to wild type mice, and express less tissue factor in the endothelium when challenged with thrombotic stimul...
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Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological condition...
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#1Elisa d’Alessandro (UM: Maastricht University)H-Index: 1
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Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and e...
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#1Iraklis C. Moschonas (UoI: University of Ioannina)H-Index: 2
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Abstract Neutrophil extracellular traps (NETs) are web-like extrusions of genetic material, which are released upon neutrophil activation. NETs consist of a chromatin substructure, onto which a vast array of proteins with various properties is dispersed. NETs production was initially described as an unrecognized defense mechanism of neutrophils, due to their ability to entrap and possibly eliminate a wide range of pathogens. Nevertheless, growing evidence suggests that NETs are implicated in a m...
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