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Bacterial infections shape cardiac macrophages’ response to ischemia

ABSTRACT: 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 scRNAseq. Nanoparticle-mediated RNAi 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 towards local origin as the primary macrophage source after infection. Profiling macrophage heterogeneity using scRNAseq, we identified two previously unknown subpopulations remaining after resolution of infection. Whereas 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 RNAi 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE301781 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:Background: Excess fibrotic remodeling leads to cardiac dysfunction in ischemic heart disease and is driven by MAP kinase-dependent transforming growth factor-ß1 (TGF-ß1) activation by coagulation signaling of myeloid cells. How coagulation-inflammatory circuits can be specifically targeted to achieve beneficial macrophage reprogramming after myocardial infarction (MI) is incompletely understood. Methods: Mice with permanent ligation of the proximal left anterior descending artery (LAD) were used to model ischemic heart disease and analyzed by single cell RNA sequencing, protein expression changes, confocal microscopy, and longitudinal monitoring of recovery. We probed the role of the tissue factor (TF)-factor 7 (F7)-integrin ß1-protease activated receptor (PAR) 2 signaling complex by utilizing genetic mouse models and pharmacological intervention. Results: Cleavage-insensitive PAR2R38E and myeloid cell integrin ß1-deficient mice had improved cardiac function after MI compared to controls. Proximity ligation assays of monocytic cells in the infarcted myocardium demonstrated that colocalization of F7 with integrin ß1 was diminished in monocyte/macrophage F7-deficient mice. F7fl/fl CX3CR1Cre relative to littermate control mice showed reduced TGF-ß1 and MAP kinase activation, as well as cardiac dysfunction after MI, despite unaltered overall recruitment of myeloid cells into the infarct zone. Single cell mRNA sequencing of CD45+ cells 3 and 7 days after MI uncovered a trajectory from ischemic myocardium-recruited monocytes to inflammatory TF+/F7+/TREM1+ macrophages. As early as 7 days after MI, macrophage F7-deletion led to an expansion of Olfml3+ macrophages with a reparative phenotype and, conversely, to a reduction of TF+/F7+/TREM1+ macrophages, which were also attenuated in activation-resistant PAR2R38E mice. To demonstrate the therapeutic potential of inhibiting the TF-F7-PAR2 signaling complex,, we injected a specific monoclonal anti-TF antibody that lacks anticoagulant activity, but interferes with macrophage migration in vitro. Short-term treatment from day 1-5 after non-reperfused MI improved cardiac dysfunction, decreased excess fibrosis, attenuated vascular endothelial dysfunction, and increased survival 28 days after MI. Conclusions: Extravascular TF-F7-PAR2 complex signaling drives inflammatory macrophage polarization in ischemic heart disease. Targeting this signaling complex for specific therapeutic macrophage reprogramming following MI attenuates cardiac fibrosis and improves cardiovascular function.

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Bacterial infections shape cardiac macrophages’ response to ischemia

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