TY - JOUR
T1 - Rapid neutrophil mobilization by VCAM-1+ endothelial cell-derived extracellular vesicles
AU - Akbar, Naveed
AU - Braithwaite, Adam T.
AU - Corr, Emma M.
AU - Koelwyn, Graeme J.
AU - van Solingen, Coen
AU - Cochain, Clément
AU - Saliba, Antoine-Emmanuel
AU - Corbin, Alastair
AU - Pezzolla, Daniela
AU - Møller Jørgensen, Malene
AU - Bæk, Rikke
AU - Edgar, Laurienne
AU - De Villiers, Carla
AU - Gunadasa-Rohling, Mala
AU - Banerjee, Abhirup
AU - Paget, Daan
AU - Lee, Charlotte
AU - Hogg, Eleanor
AU - Costin, Adam
AU - Dhaliwal, Raman
AU - Johnson, Errin
AU - Krausgruber, Thomas
AU - Riepsaame, Joey
AU - Melling, Genevieve E.
AU - Shanmuganathan, Mayooran
AU - Oxford Acute Myocardial Infarction Study (OxAMI)
AU - Bock, Christoph
AU - Carter, David R. F
AU - Channon, Keith M.
AU - Riley, Paul R.
AU - Udalova, Irina A.
AU - Moore, Kathryn J.
AU - Anthony, Daniel
AU - Choudhury, Robin P.
N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - 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.
AB - 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.
KW - Exosome
KW - Myocardial infarction
KW - Programming
KW - Spleen
UR - http://www.scopus.com/inward/record.url?scp=85150665330&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvac012
DO - 10.1093/cvr/cvac012
M3 - Journal article
C2 - 35134856
SN - 0008-6363
VL - 119
SP - 236
EP - 251
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
M1 - cvac012
ER -