Nature or Nurture? The driving force of macrophage behaviors in the ischemic and non-ischemic cardiac injuries.

Tamara Antonela Vico (Freiburg im Breisgau)1, G. Witte (Freiburg im Breisgau)1, M. Taglinger (Freiburg im Breisgau)1, V. Haacke (Freiburg im Breisgau)1, S. Perez Feliz (Freiburg im Breisgau)2, B. Dufner (Freiburg im Breisgau)1, C. Koentges (Freiburg im Breisgau)3, T.-S. Dederichs (Freiburg im Breisgau)1, A. von Ehr (Freiburg im Breisgau)1, D. Westermann (Freiburg im Breisgau)1, I. Hilgendorf (Freiburg im Breisgau)1

1Universitäts-Herzzentrum Freiburg - Bad Krozingen Freiburg im Breisgau, Deutschland; 2Universitäts-Herzzentrum Freiburg - Bad Krozingen Institut für Experimentelle Kardiovaskuläre Medizin Freiburg im Breisgau, Deutschland; 3Institute for Disease Modelling and Targeted Medicine (IMITATE) Freiburg im Breisgau, Deutschland



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. 

In the ischemic injury, recruited macrophages showed increased cytokine synthesis, defensive response, and cell adhesion pathways during the first week after injury, and remained upregulated at day 28 despite simultaneous activation of the anti-inflammatory response. Resident macrophages also expressed immune response activation throughout the healing process. Thus, in accordance with cell numbers distribution at day 28, macrophage populations converted into the same phenotype, a new pro-inflammatory steady state, independently of their ontogenetic origin, and different from the healthy heart. However, in the remote zone, resident macrophages maintained cellular homeostasis function, unlike recruited macrophages that remained with their inflammatory program. On the contrary, after TAC surgery, transcriptional profiles remained differentially regulated between recruited and resident cardiac macrophages at all time points tested, where recruited subset induced immune response and resident macrophages upregulated tissue remodeling genes.


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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