1. Academic Validation
  2. Neutrophil "plucking" on megakaryocytes drives platelet production and boosts cardiovascular disease

Neutrophil "plucking" on megakaryocytes drives platelet production and boosts cardiovascular disease

  • Immunity. 2022 Oct 18;S1074-7613(22)00542-8. doi: 10.1016/j.immuni.2022.10.001.
Tobias Petzold 1 Zhe Zhang 2 Iván Ballesteros 3 Inas Saleh 4 Amin Polzin 5 Manuela Thienel 4 Lulu Liu 4 Qurrat Ul Ain 4 Vincent Ehreiser 4 Christian Weber 4 Badr Kilani 4 Pontus Mertsch 6 Jeremias Götschke 6 Sophie Cremer 5 Wenwen Fu 7 Michael Lorenz 2 Hellen Ishikawa-Ankerhold 4 Elisabeth Raatz 7 Shaza El-Nemr 4 Agnes Görlach 8 Esther Marhuenda 9 Konstantin Stark 4 Joachim Pircher 4 David Stegner 10 Christian Gieger 11 Marc Schmidt-Supprian 12 Florian Gaertner 13 Isaac Almendros 14 Malte Kelm 5 Christian Schulz 4 Andrés Hidalgo 15 Steffen Massberg 16
Affiliations

Affiliations

  • 1 Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany; Partner site Munich Heart Alliance, DZHK (German Centre for Cardiovascular Research), 80802 Munich, Germany; Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany. Electronic address: [email protected]
  • 2 Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany; Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany.
  • 3 Program of Cardiovascular Regeneration, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
  • 4 Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany; Partner site Munich Heart Alliance, DZHK (German Centre for Cardiovascular Research), 80802 Munich, Germany; Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany.
  • 5 Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID), Medical Faculty of the Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • 6 Medizinische Klinik und Poliklinik V, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany; Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), 81377 Munich, Germany.
  • 7 Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany.
  • 8 Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University of Munich, 80636 Munich, Germany; Partner site Munich Heart Alliance, DZHK (German Centre for Cardiovascular Research), 80802 Munich, Germany.
  • 9 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08007 Barcelona, Spain.
  • 10 Institute of Experimental Biomedicine, University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging, 97070 Würzburg, Germany.
  • 11 Research Unit Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
  • 12 Institute of Experimental Hematology, School of Medicine, Technical University Munich, 80333 Munich, Germany; Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich 81675, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69117 Heidelberg, Germany.
  • 13 Institute of Science and Technology Austria, 3400 Klosterneuburg, Austria.
  • 14 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08007 Barcelona, Spain; CIBER de Enfermedades Respiratorias, 28029 Madrid, Spain.
  • 15 Program of Cardiovascular Regeneration, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; Vascular Biology and Therapeutics Program and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 16 Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany; Partner site Munich Heart Alliance, DZHK (German Centre for Cardiovascular Research), 80802 Munich, Germany; Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, Klinikum der Universität München, Ludwig-Maximilians- University Munich, 81377 Munich, Germany. Electronic address: [email protected]
Abstract

Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered Myosin light chain and extracellular-signal-regulated kinase activation through Reactive Oxygen Species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events.

Keywords

bone marrow; mechanotransduction; neutrophils; thromboinflammation; thrombopoiesis; thrombosis.

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