Bacterial Infections Shape Cardiac Macrophages' Response to Ischemia

BACKGROUND: Patients with bacterial infections are at increased risk for subsequent cardiovascular events. Whether infections' effects on innate immune cells within the cardiovascular system influence subsequent pathologies remains unclear. Here, we explore cardiac myeloid cells' chronic adaptations to a preceding bacterial insult and implications for subsequent myocardial ischemia. METHODS: We used various flow cytometry protocols to assess cardiac immune cells, peripheral leukocytes, and hematopoietic stem and progenitor cells in bone marrow and spleen. A genetic fate-mapping model was used to determine cardiac macrophages' origin after bacteremia. Cardiac leukocytes were analyzed using single-cell RNA sequencing. Nanoparticle-mediated RNA interference was used to target macrophages in vivo. RESULTS: Cardiac macrophage numbers increased sharply, and numerical changes alongside subset alterations persisted over time. Fate-mapping pointed toward local origin as the primary macrophage source after infection. Profiling macrophage heterogeneity using single-cell RNA sequencing, we identified two previously unknown subpopulations remaining after resolution of infection. While heightened metabolic activity was one subset's primary feature, the other displayed excessive chemotactic properties, which amplified cardiac leukocyte recruitment and inflammation after a subsequent ischemic injury. Targeting cardiac macrophages' surplus inflammatory activity after infection using nanoparticle-enabled, macrophage-directed RNA interference kept disproportionate subsequent ischemic inflammation at bay. CONCLUSIONS: Bacteremia induces long-lasting changes in the cardiovascular system's innate immune cells' composition. This may amplify myocardial inflammation after a subsequent ischemic injury.