Endothelium-derived extracellular vesicles promote splenic monocyte mobilization in myocardial infarction.

Naveed Akbar,Laurienne Edgar,Nadiia Rawlings,Daniel C Anthony,Irina A Udalova,Janet E Digby,Errin Johnson,David R Greaves,Mala Rohling,T Grant Belgard,Paul R Riley,Eileen Mcneill,Thomas J Cahill,Keith M Channon,Sam Dawkins,Aniket Tavare ,Alastair Corbin ,Alaa A A Aljabali ,Sonia Saluja ,Rebecca Dragovic ,Klemen Žiberna ,R P Choudhury

doi:10.1172/jci.insight.93344

Abstract

Transcriptionally activated monocytes are recruited to the heart after acute myocardial infarction (AMI). After AMI in mice and humans, the number of extracellular vesicles (EVs) increased acutely. In humans, EV number correlated closely with the extent of myocardial injury. We hypothesized that EVs mediate splenic monocyte mobilization and program transcription following AMI. Some plasma EVs bear endothelial cell (EC) integrins, and both proinflammatory stimulation of ECs and AMI significantly increased VCAM-1–positive EV release. Injected EC-EVs localized to the spleen and interacted with, and mobilized, splenic monocytes in otherwise naive, healthy animals. Analysis of human plasma EV-associated miRNA showed 12 markedly enriched miRNAs after AMI; functional enrichment analyses identified 1,869 putative mRNA targets, which regulate relevant cellular functions (e.g., proliferation and cell movement). Furthermore, gene ontology termed positive chemotaxis as the most enriched pathway for the miRNA-mRNA targets. Among the identified EV miRNAs, EC-associated miRNA-126-3p and -5p were highly regulated after AMI. miRNA-126-3p and -5p regulate cell adhesion– and chemotaxis-associated genes, including the negative regulator of cell motility, plexin-B2. EC-EV exposure significantly downregulated plexin-B2 mRNA in monocytes and upregulated motility integrin ITGB2. These findings identify EVs as a possible novel signaling pathway by linking ischemic myocardium with monocyte mobilization and transcriptional activation following AMI.

Highlights

Tissue injury sustained after acute myocardial infarction (AMI) results in local necrosis and inflammation
extracellular vesicles (EVs) size distribution was similar across all time points, with a specific increase in exosome number (EV
We found that there is a contribution of bone marrow monocytes to the peripheral monocytosis (Figure 6E) that occurs after i.v. injection of endothelial cell (EC)-EVs. (1.44-fold, P < 0.01)

Summary

Introduction

Tissue injury sustained after acute myocardial infarction (AMI) results in local necrosis and inflammation. AMI induces a peripheral monocytosis in both humans and mice, which is positively correlated with the extent of myocardial injury [1]. Recent pivotal studies have shown that activation of the innate immune system in AMI sequentially mediates aspects of both injury and repair [1,2,3,4]. A better understanding of the processes involved in monocyte activation and recruitment to the damaged myocardium might allow therapeutic intervention to alter favorably the milieu for repair and regeneration and to extend the very short time window of efficacy for current treatments of AMI. We have recently shown that, in both mice and humans, AMI is associated with distinct patterns of gene expression in monocytes, which are conserved between species [1]

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