Rapid neutrophil mobilization by VCAM-1+ endothelial cell-derived extracellular vesicles

Author:

Akbar Naveed1ORCID,Braithwaite Adam T1ORCID,Corr Emma M2,Koelwyn Graeme J2,van Solingen Coen2ORCID,Cochain Clément3ORCID,Saliba Antoine-Emmanuel4,Corbin Alastair5ORCID,Pezzolla Daniela1ORCID,Møller Jørgensen Malene67ORCID,Bæk Rikke7ORCID,Edgar Laurienne1ORCID,De Villiers Carla8,Gunadasa-Rohling Mala8ORCID,Banerjee Abhirup1ORCID,Paget Daan1ORCID,Lee Charlotte1ORCID,Hogg Eleanor1ORCID,Costin Adam9ORCID,Dhaliwal Raman9ORCID,Johnson Errin9,Krausgruber Thomas10ORCID,Riepsaame Joey9ORCID,Melling Genevieve E1112,Shanmuganathan Mayooran11314,Banning Adrian,Kharbanda Raj,Ruparelia Neil,Alkhalil Mohammad,De Maria GianLiugi,Gaughran Lisa,Dall’Armellina Erica,Ferreira Vanessa,Borlotti Alessandra,Ng Yujun,Bock Christoph1015ORCID,Carter David R F11,Channon Keith M11314,Riley Paul R8ORCID,Udalova Irina A5,Moore Kathryn J2ORCID,Anthony Daniel C16ORCID,Choudhury Robin P11314ORCID,

Affiliation:

1. Division of Cardiovascular Medicine, Radcliffe Department of Medicine University of Oxford Level 6, West Wing John Radcliffe Hospital Headington Oxford OX3 9DU , UK

2. NYU Cardiovascular Research Center, Department of Medicine, Division of Cardiology, School of Medicine, New York University School of Medicine , 435 E 30th St. New York, NY 10016 , USA

3. Comprehensive Heart Failure Center, University Hospital Wurzburg, Anstalt des öffentlichen Rechts Josef-Schneider-Straße 2 97080 Würzburg , Germany

4. Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Inhoffenstraße 7 38124 Braunschweig, Würzburg , Germany

5. Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Dr, Headington , Oxford OX3 7FY , UK

6. Department of Clinical Immunology, Aalborg University Hospital , Urbansgade 32-36, DK-9000, Aalborg , Denmark

7. Department of Clinical Medicine, Aalborg University , Søndre Skovvej 15, Aalborg , Denmark

8. Department of Physiology, Anatomy and Genetics, University of Oxford , Sherrington Building Parks Road, OX1 3PT, Oxford , UK

9. Sir William Dunn School of Pathology, University of Oxford, South Parks Road , Oxford, OX1 3RE , UK

10. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences , Lazarettgasse 14, AKH BT 25.3, Vienna , Austria

11. Department of Biological and Medical Sciences, Oxford Brookes University , Headington Campus Oxford OX3 0BP , UK

12. Institute of Clinical Sciences, School of Biomedical Sciences, College of Medical and Dental Sciences, University of Birmingham , Edgbaston, Birmingham, B15 2TT , UK

13. The OxAMI Study is detailed in the Supplementary Acknowledgments

14. Acute Vascular Imaging Centre, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington , Oxford, OX3 9DU , UK

15. Institute of Artificial Intelligence, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna , Spitalgasse 23, BT88 1090, Vienna , Austria

16. Department of Pharmacology, University of Oxford , Mansfield Road, Oxford, OX1 3QT , UK

Abstract

Abstract Aims Acute myocardial infarction rapidly increases blood neutrophils (<2 h). Release from bone marrow, in response to chemokine elevation, has been considered their source, but chemokine levels peak up to 24 h after injury, and after neutrophil elevation. This suggests that additional non-chemokine-dependent processes may be involved. Endothelial cell (EC) activation promotes the rapid (<30 min) release of extracellular vesicles (EVs), which have emerged as an important means of cell–cell signalling and are thus a potential mechanism for communicating with remote tissues. Methods and results Here, we show that injury to the myocardium rapidly mobilizes neutrophils from the spleen to peripheral blood and induces their transcriptional activation prior to arrival at the injured tissue. Time course analysis of plasma-EV composition revealed a rapid and selective increase in EVs bearing VCAM-1. These EVs, which were also enriched for miRNA-126, accumulated preferentially in the spleen where they induced local inflammatory gene and chemokine protein expression, and mobilized splenic-neutrophils to peripheral blood. Using CRISPR/Cas9 genome editing, we generated VCAM-1-deficient EC-EVs and showed that its deletion removed the ability of EC-EVs to provoke the mobilization of neutrophils. Furthermore, inhibition of miRNA-126 in vivo reduced myocardial infarction size in a mouse model. Conclusions Our findings show a novel EV-dependent mechanism for the rapid mobilization of neutrophils to peripheral blood from a splenic reserve and establish a proof of concept for functional manipulation of EV-communications through genetic alteration of parent cells.

Funder

British Heart Foundation (BHF) Centre of Research Excellence, Oxford

British Heart Foundation Project Grant

Tripartite Immunometabolism Consortium, Novo Nordisk Foundation

Oxford Biomedical Research Centre

Nuffield Benefaction for Medicine and the Wellcome Institutional Strategic Support Fund (ISSF)

National Institutes of Health

American Heart Association

Biotechnology and Biological Sciences Research Council

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

Reference52 articles.

1. The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment;Schloss;EMBO Mol Med,2016

2. Prognostic value of neutrophil to lymphocyte ratio for in-hospital mortality in elderly patients with acute myocardial infarction;Guo;Curr Med Sci,2018

3. Usefulness of the delta neutrophil index to predict 30-day mortality in patients with ST segment elevation myocardial infarction;Kong;Sci Rep,2017

4. Neutrophil-derived S100A8/A9 amplify granulopoiesis after myocardial infarction;Sreejit;Circulation,2020

5. Association of leukocyte and neutrophil counts with infarct size, left ventricular function and outcomes after percutaneous coronary intervention for ST-elevation myocardial infarction;Chia;Am J Cardiol,2009

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