In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody–Mediated Venous Thrombosis

Arthritis and Rheumatology - Tập 69 Số 3 - Trang 655-667 - 2017
He Meng1,2, Srilakshmi Yalavarthi1,2, Yogendra Kanthi3,4, Levi F. Mazza1,2, Megan Elfline5, Catherine E. Luke5, David J. Pinsky3, Peter K. Henke5, Jason S. Knight1,2
1Rheumatology and
2University of Michigan Medical School, Ann Arbor
3Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School;
4University of Michigan Medical School and Ann Arbor Veterans Administration Healthcare System Ann Arbor
5Department of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA

Tóm tắt

ObjectiveAntiphospholipid syndrome (APS) is a leading acquired cause of thrombotic events. Although antiphospholipid antibodies have been shown to promote thrombosis in mice, the role of neutrophils has not been explicitly studied. The aim of this study was to characterize neutrophils in the context of a new model of antiphospholipid antibody–mediated venous thrombosis.MethodsMice were administered fractions of IgG obtained from patients with APS. At the same time, blood flow through the inferior vena cava was reduced by induction of stenosis. Resulting thrombi were characterized for size and neutrophil content. Circulating factors and the vessel wall were also assessed.ResultsAs measured by both thrombus weight and thrombosis frequency, mice treated with IgG from patients with APS (APS IgG) demonstrated exaggerated thrombosis as compared with control IgG–treated mice. Thrombi in mice treated with APS IgG were enriched for citrullinated histone H3 (a marker of neutrophil extracellular traps [NETs]). APS IgG–treated mice also demonstrated elevated levels of circulating cell‐free DNA and human IgG bound to the neutrophil surface. In contrast, circulating neutrophil numbers and markers of vessel wall activation were not appreciably different between APS IgG–treated mice and control mice. Treatment with either DNase (which dissolves NETs) or a neutrophil‐depleting antibody reduced thrombosis in APS IgG–treated mice to the level in control mice.ConclusionThese data support a mechanism whereby circulating neutrophils are primed by antiphospholipid antibodies to accelerate thrombosis. This line of investigation suggests new, immunomodulatory approaches for the treatment of APS.

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Tài liệu tham khảo

10.1016/j.jaut.2014.01.006

10.1016/j.autrev.2014.05.001

10.1016/j.autrev.2015.01.002

10.1055/s-0032-1311827

10.1093/rheumatology/keu360

10.1136/ard.2006.065037

10.1002/art.21157

10.1182/blood-2010-08-300715

10.1182/blood-2014-02-554980

10.1177/0961203315603146

10.1002/art.10187

10.1016/S0140-6736(10)60709-X

10.1056/NEJMra1112830

10.1038/nrrheum.2011.52

10.1182/blood-2005-03-1319

10.1002/art.39247

Leffler J, 2014, Degradation of neutrophil extracellular traps is decreased in patients with antiphospholipid syndrome, Clin Exp Rheumatol, 32, 66

den Hoogen LL, 2016, Low‐density granulocytes are increased in antiphospholipid syndrome and are associated with anti–β2‐glycoprotein I antibodies: comment on the article by Yalavarthi et al [letter], Arthritis Rheumatol, 68, 1320, 10.1002/art.39576

10.1182/blood-2013-10-463646

10.1126/science.1092385

10.1083/jcb.201203170

10.1084/jem.20112322

10.1161/ATVBAHA.114.304114

10.1073/pnas.1005743107

10.1371/journal.pone.0045427

10.1111/j.1538-7836.2011.04544.x

10.1111/j.1538-7836.2006.01753.x

10.1002/art.1780400928

10.1111/j.1538-7836.2009.03555.x

10.1016/j.jvs.2015.08.070

Kanthi Y, 2016, Flow‐dependent expression of ectonucleotide tri(di)phosphohydrolase‐1 and suppression of atherosclerosis, J Clin Invest, 64, 1450

10.1172/JCI67390

10.1136/annrheumdis-2014-205365

10.1136/jcp.27.7.517

10.1038/nrrheum.2015.96

10.4330/wjc.v7.i12.829

10.1161/01.CIR.96.12.4380

10.1016/j.blre.2009.07.002

10.1038/nm1565

10.1172/JCI61303

10.1016/j.febslet.2010.06.006

10.1191/096120398678920037

10.1046/j.1365-2249.1996.d01-839.x

10.1191/096120399678847380

10.1073/pnas.1301059110

10.1172/JCI67484

Grenn RC, 2016, Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome, Ann Rheum Dis

10.1016/j.thromres.2016.01.009

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Arthritis and Rheumatology

Tập 69 Số 3

655-667

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