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

Naveed Akbar, Adam T. Braithwaite, Emma M. Corr, Graeme J. Koelwyn, Coen van Solingen, Clément Cochain, Antoine-Emmanuel Saliba, Alastair Corbin, Daniela Pezzolla, Malene Møller Jørgensen, Rikke Bæk, Laurienne Edgar, Carla De Villiers, Mala Gunadasa-Rohling, Abhirup Banerjee, Daan Paget, Charlotte Lee, Eleanor Hogg, Adam Costin, Raman DhaliwalErrin Johnson, Thomas Krausgruber, Joey Riepsaame, Genevieve E. Melling, Mayooran Shanmuganathan, Oxford Acute Myocardial Infarction Study (OxAMI), Christoph Bock, David R. F Carter, Keith M. Channon, Paul R. Riley, Irina A. Udalova, Kathryn J. Moore, Daniel Anthony, Robin P. Choudhury*

*Kontaktforfatter

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

16 Citationer (Scopus)
14 Downloads (Pure)

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.

OriginalsprogEngelsk
Artikelnummercvac012
TidsskriftCardiovascular Research
Vol/bind119
Udgave nummer1
Sider (fra-til)236-251
Antal sider16
ISSN0008-6363
DOI
StatusUdgivet - 1 jan. 2023

Bibliografisk note

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

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