Recruited macrophages incorporate into the resident cardiac macrophage pool and converge into a common phenotype in the healing infarct, but not in the failing heart exposed to pressure overload

Abstract

Abstract 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 We use a tamoxifen inducible CX3CR1 Yfp 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. 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 and at 8 weeks post TAC. In I/R injury, the 1:1 equilibrium established already during the first week in the remote myocardium. Gene expression profiles changed alongside shifts in macrophage ratios. For instance, in the infarct, recruited macrophages showed upregulation of cytokine production and cell chemotaxis pathways at early stage. By 4 weeks post MI their gene expression profiles have converged with those of resident macrophages. Likewise, in the remote myocardium, recruited and resident macrophages assimilated post MI, overexpressing genes associated adaptative immune response activation and cellular homeostasis. Similar to the I/R injury setting, a 1:1 equilibrium of resident and recruited macrophages established in the hypertrophied and dilated hearts within 4 to 8 weeks post 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: recruited macrophages behavior changed from a profibrotic into a proliferative phenotype, meanwhile resident macrophages featured prominently in tissue homeostasis. 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 remodeling tissue determine partial or complete override of ontogenic cell programs.