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      Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome

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          Abstract

          Potentiation of neutrophil extracellular trap (NET) release is one mechanism by which antiphospholipid antibodies (aPL Abs) effect thrombotic events in patients with antiphospholipid syndrome (APS). Surface adenosine receptors trigger cyclic AMP (cAMP) formation in neutrophils, and this mechanism has been proposed to regulate NETosis in some contexts. Here we report that selective agonism of the adenosine A 2A receptor (CGS21680) suppresses aPL Ab-mediated NETosis in protein kinase A-dependent fashion. CGS21680 also reduces thrombosis in the inferior vena cavae of both control mice and mice administered aPL Abs. The antithrombotic medication dipyridamole is known to potentiate adenosine signaling by increasing extracellular concentrations of adenosine and interfering with the breakdown of cAMP. Like CGS21680, dipyridamole suppresses aPL Ab-mediated NETosis via the adenosine A 2A receptor and mitigates venous thrombosis in mice. In summary, these data suggest an anti-inflammatory therapeutic paradigm in APS, which may extend to thrombotic disease in the general population.

          Abstract

          Antiphospholipid syndrome is characterised by increased neutrophil extracellular trap formation (NETosis) and, consequently, increased thrombotic events. Here Ali et al. show that treatment with adenosine receptor agonists suppresses NETosis and venous thrombosis in mouse models of antiphospholipid syndrome.

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          Most cited references64

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          International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).

          New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies. In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum. Based on this, we propose amendments to the Sapporo criteria. We also provide definitions on features of APS that were not included in the updated criteria.
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            Netting neutrophils in autoimmune small-vessel vasculitis.

            Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.
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              Extracellular DNA traps promote thrombosis.

              Neutrophil extracellular traps (NETs) are part of the innate immune response to infections. NETs are a meshwork of DNA fibers comprising histones and antimicrobial proteins. Microbes are immobilized in NETs and encounter a locally high and lethal concentration of effector proteins. Recent studies show that NETs are formed inside the vasculature in infections and noninfectious diseases. Here we report that NETs provide a heretofore unrecognized scaffold and stimulus for thrombus formation. NETs perfused with blood caused platelet adhesion, activation, and aggregation. DNase or the anticoagulant heparin dismantled the NET scaffold and prevented thrombus formation. Stimulation of platelets with purified histones was sufficient for aggregation. NETs recruited red blood cells, promoted fibrin deposition, and induced a red thrombus, such as that found in veins. Markers of extracellular DNA traps were detected in a thrombus and plasma of baboons subjected to deep vein thrombosis, an example of inflammation-enhanced thrombosis. Our observations indicate that NETs are a previously unrecognized link between inflammation and thrombosis and may further explain the epidemiological association of infection with thrombosis.
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                Author and article information

                Contributors
                +734-936-3257 , jsknight@umich.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                23 April 2019
                23 April 2019
                2019
                : 10
                : 1916
                Affiliations
                [1 ]ISNI 0000000086837370, GRID grid.214458.e, Division of Rheumatology, Department of Internal Medicine, , University of Michigan, ; Ann Arbor, MI 48109 USA
                [2 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Biomedical Engineering, , University of Michigan, ; Ann Arbor, MI 48109 USA
                [3 ]ISNI 0000000086837370, GRID grid.214458.e, Division of Hematology and Oncology, Department of Internal Medicine, , University of Michigan Medical School, ; Ann Arbor, MI 48109 USA
                [4 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Molecular and Integrative Physiology, , University of Michigan, ; Ann Arbor, MI 48109 USA
                [5 ]ISNI 0000000086837370, GRID grid.214458.e, Division of Cardiovascular Medicine, Department of Internal Medicine, , University of Michigan, ; Ann Arbor, MI 48109 USA
                [6 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Vascular Surgery, , University of Michigan, ; Ann Arbor, MI 48109 USA
                [7 ]Division of Cardiology, Ann Arbor Veterans Administration Healthcare System, Ann Arbor, MI 48109 USA
                Article
                9801
                10.1038/s41467-019-09801-x
                6478874
                31015489
                ee098f33-bfdf-45f9-b7db-22bc48f29b1a
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 July 2018
                : 29 March 2019
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                autoimmunity,neutrophils,thrombosis,antiphospholipid syndrome
                Uncategorized
                autoimmunity, neutrophils, thrombosis, antiphospholipid syndrome

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