Extracellular Vesicles Mediate Activation and Trafficking of Splenic Immune Cells to the Heart Post-Myocardial Infarction

Abstract

BackgroundMyocardial infarction (MI) triggers splenic immune cell trafficking to the heart. Vehicles that carry these signals and mediate this crosstalk are unknown. HypothesisWe hypothesize that extracellular vesicles (EVs) released post-MI mediate splenic immune trafficking to the heart. MethodsMice were treated daily with an EV biogenesis inhibitor (GW4869) or vehicle. Splenic/cardiac immune cells were assessed at 3d while survival, cardiac function, hypertrophy, and fibrosis were evaluated at 8w post-MI. Plasma EVs from 1d MI mice or from the hearts that underwent MI/sham in a Langendorff system induced splenic immune trafficking to the heart within 3d and systolic dysfunction at 8w in naive mice. ResultsGW4869 i) inhibited splenic regression, ii) increased splenic retention of neutrophils, monocytes, dendritic cells (DCs), and CD4 T-cells, iii) decreased cardiac gene expression of pro-inflammatory cytokines/chemokines, and iv) decreased trafficking of immune cells to the hearts at 3d post-MI, and iii) improved systolic function and attenuated hypertrophy at 8w post-MI. MI EVs accumulated in the spleen and promoted egress of matured splenic immune cells upon administration to naive mice. Cardiac pro-inflammatory cytokines/chemokines expression and CCR2+MHC-IIhi infiltrating macrophages, CD11c+ DCs, and CD4+ and CD4+TNF+ T-cell levels were also increased in naive mice at 3d post-injection. Importantly, transfer of MI EVs for 2 days induced systolic dysfunction, cellular hypertrophy, and fibrosis in naive mice at 8 w post-injection. DCs process MI EVs for T-cells activation. ConclusionsEVs mobilize splenic immune cells to the heart post-MI and their inhibition can subdue inflammatory tissue-damage to promote healing post-MI.