Abstract 777 Recruited and resident cardiac macrophage phenotypes converge in the healing infarct but not in the failing heart exposed to continuous pressure overload.

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
Recruited and resident cardiac macrophage phenotypes converge in the healing infarct but not in the failing heart exposed to continuous pressure overload.
T. Vico¹, M. Taglinger¹, V. Haacke¹, B. Dufner¹, C. Zehender¹, B. Heinz¹, A. von Ehr¹, D. Westermann¹, I. Hilgendorf²
¹Innere Medizin III, Kardiologie und Angiologie, Universitäts-Herzzentrum Freiburg - Bad Krozingen, Freiburg im Breisgau; ²Klinik für Kardiologie und Angiologie I, Universitäts-Herzzentrum Freiburg - Bad Krozingen, Freiburg im Breisgau;
Introduction: Resident macrophages account for 5% of the cells in the healthy heart. In response to cardiac injury, monocytes infiltrate and differentiate into recruited macrophages which function distinctly from the resident subset of primarily embryonic origin. In this work, we aim to identify the extent to which macrophage origin, tissue location and type of cardiac injury determine macrophage phenotypes in ischemic and non-ischemic cardiac injuries over time. Results and methods: To this end, we use a tamoxifen inducible CX3CR1Yfp CreER/+:R26tdT/+ mouse line to visualize and quantify fluxes of resident and recruited macrophages and their respective localizations within the heart following ischemia and reperfusion (I/R) injury and pressure overload after transversal aortic constriction (TAC), respectively. While I/R represents an acute cardiac injury, TAC increases cardiac afterload continuously. Interestingly, macrophage numbers peaked during the first week post-surgery in both the local/acute and the global/continuous injury models. Initially, recruited macrophages outnumbered the resident macrophage pool within the infarct area but ultimately reached a 1:1 equilibrium at 4 weeks post I/R injury. In the remote myocardium the 1:1 equilibrium established already during the first week. In TAC-injured hearts, the 1:1 ratio of recruited and resident hearts also established within the first week post-surgery and continued up to 8 weeks of follow-up even as cardiac macrophage numbers declined and cardiac function deteriorated. Gene expression analysis of resident and recruited cardiac macrophages obtained from the infarct and remote areas at different time points post I/R injury identified differential expression profiles (e.g. inflammation, migration, proliferation) within the first week post injury. Unexpectedly, the transcriptional changes converged at a new, healed steady state profile shared by both recruited and resident cardiac macrophages, but distinct from the uninjured heart. After TAC surgery, however, transcriptional profiles remained differentially regulated between recruited and resident cardiac macrophages at all time points tested, and distinct from those observed post I/R injury. Conclusion: Ischemic and non-ischemic, focal and global, acute and chronic cardiac injuries induce a transient peak of monocyte recruitment and macrophage differentiation in and around cardiac lesions which lead to a permanent integration of recruited monocyte-derived macrophages into the pool of tissue resident macrophages – albeit at different paces. The type of injury and macrophage localization within the changing tissue microenvironment determine partial or complete override of ontogenic cell programs.
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