Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo

Author:

von Brühl Marie-Luise12,Stark Konstantin12,Steinhart Alexander12,Chandraratne Sue12,Konrad Ildiko12,Lorenz Michael12,Khandoga Alexander12,Tirniceriu Anca12,Coletti Raffaele12,Köllnberger Maria12,Byrne Robert A.12,Laitinen Iina1,Walch Axel3,Brill Alexander4,Pfeiler Susanne5,Manukyan Davit5,Braun Siegmund1,Lange Philipp5,Riegger Julia12,Ware Jerry6,Eckart Annekathrin12,Haidari Selgai12,Rudelius Martina1,Schulz Christian127,Echtler Katrin12,Brinkmann Volker8,Schwaiger Markus1,Preissner Klaus T.9,Wagner Denisa D.4,Mackman Nigel10,Engelmann Bernd5,Massberg Steffen12

Affiliation:

1. Deutsches Herzzentrum and I. Medizinische Klinik, Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, and Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München (TUM), 80333 Munich, Germany

2. Munich Heart Alliance, Munich, Germany

3. Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, Institut für Pathologie, 85764 Neuherberg, Germany

4. Immune Disease Institute, Program in Cellular and Molecular Medicine, Children’s Hospital, Boston, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115

5. Institut für Klinische Chemie and Medizinische Klinik I, Ludwig-Maximilians-Universität, 81377 Munich, Germany

6. Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205

7. Centre for Molecular and Cellular Biology of Inflammation, King’s College London, London SE1 1UL, UK

8. Max-Planck-Institut für Infektionsbiologie, 10117 Berlin, Germany

9. Department of Biochemistry, University of Giessen, 35392 Giessen, Germany

10. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514

Abstract

Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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