Extracellular Vesicles Mediate Activation and Trafficking of Splenic Immune Cells to the Heart Post-Myocardial Infarction
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Myocardial infarction (MI) triggers splenic immune cell trafficking to the heart. Vehicles that carry these signals and mediate this crosstalk are unknown.
Hypothesis
We hypothesize that extracellular vesicles (EVs) released post-MI mediate splenic immune trafficking to the heart.
Methods
Mice 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 naïve mice.
Results
GW4869 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 naïve mice. Cardiac pro-inflammatory cytokines/chemokines expression and CCR2 + MHC-II hi infiltrating macrophages, CD11c + DCs, and CD4 + and CD4 + TNFα + T-cell levels were also increased in naïve mice at 3d post-injection. Importantly, transfer of MI EVs for 2 days induced systolic dysfunction, cellular hypertrophy, and fibrosis in naïve mice at 8 w post-injection. DCs process MI EVs for T-cells activation.
Conclusions
EVs mobilize splenic immune cells to the heart post-MI and their inhibition can subdue inflammatory tissue-damage to promote healing post-MI.
