Exosomes mediate immune activation post-myocardial infarction

Myocardial infarction (MI) and ischemic heart failure (HF) are associated with immune activation in the bone-marrow and the lymphoid tissues. Our studies also show that spleens lose 58% of their weight by 1-day post-MI as compared to sham-operation. Flow cytometric analysis further showed that, as compared to sham-operated mice, spleens of 1d post-MI mice contained 2-3-fold lower numbers of leukocytes (16.9X10 6 vs. 47.7X10 6 ), CD11c + dendritic cells (DCs; 0.22X10 6 vs. 0.56X10 6 ), Ly6G + neutrophils (0.45X10 6 vs. 1.08X10 6 ), CD11b + myeloid cells (1.2X10 6 vs. 2.8X10 6 ), and Ly6C + monocytes (0.4X10 6 vs. 1.0X10 6 ). Activation of antigen-presenting innate immune cells would also suggest activation of adaptive immune responses. Thus, using flow cytometry we also measured CD4 + and CD8 + T-cells in the spleens of 1d MI and sham mice and found that both of these cell types (2.2X10 6 vs. 5.7X10 6 for CD4 + T-cells and 1.5X10 6 vs. 3.8X10 6 for CD8 + cytotoxic T-cells) were also decreased. These data suggest that damage-associated signals from the infarcted heart are communicated to the splenic innate and adaptive immune cells leading to their efflux and trafficking to the heart. However, the communication vehicles that relay these damage-associated signals from the heart to the spleen are unknown. We further hypothesized that these signals are carried by the exosomes, small (100-200 nm) extracellular vesicles released by all cells. To test our hypothesis, we isolated exosomes from the plasma of 1d MI and sham mice, injected them into the tail-veins of naïve mice and using echocardiography measured their cardiac function at 8 weeks post-injection to assess if they developed HF-like systolic dysfunction. We found that, at 8 weeks, mice injected with 1d MI exosomes developed significant systolic dysfunction with increased end-systolic and end-diastolic volumes, and decreased ejection fraction. These changes were not seen in mice injected with 1d sham exosomes. Further, using flow cytometry we also measured different splenic immune cells in the recipient mice. Our data show that spleens of mice injected with 1d MI exosomes, as compared to 1d sham exosomes, contained higher numbers of activated immune cells and showed increased levels of proinflammatory monocytes (without any changes in anti-inflammatory monocytes), CD11c + conventional and monocyte-derived DCs and helper T-cell subsets such as T-regs, Th1, Th2, Th17. Our results suggest that exosomal signals could be a novel potential mechanism by which cardiac injury is communicated to the lymphoid tissues to affect immune cell recruitment following MI. This work was supported by the National Institutes of Health grants to. Dr Shyam S. Bansal (R00 HL132123 and R01 HL153164). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.