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 complementing the original resident macrophage population and their progeny. Overall macrophages decisively orchestrate cardiac remodeling.We aim to determine how macrophage origin, tissue location, and the type of cardiac injury shape macrophage phenotypes over time in ischemic and non-ischemic hearts, linking these dynamics to maladaptive remodeling and heart failure risk.
Results and methods:
Using a tamoxifen inducible CX3CR1Yfp CreER/+:R26tdT/+ mouse model, we visualized and quantified the dynamics of the resident and recruited macrophages in ischemia and reperfusion (I/R) injury and pressure overload after transversal aortic constriction (TAC) models. I/R represents an acute, localized injury, while TAC increases cardiac afterload continuously and affects the heart globally. Initially, recruited macrophages outnumbered the resident macrophage pool within the infarct area but ultimately reached a near 1:1 equilibrium at 4 weeks post I/R injury. In contrast, in the remote myocardium and TAC-injured hearts, this equilibrium was established within the first week and persisted as cardiac function declined. In the infarct, recruited macrophages transcriptomics exhibited elevated cytokine synthesis and inflammatory responses that remained active up to day 28 post-MI. Interestingly, by day 28, both macrophage populations converged onto a shared phenotype. In the remote myocardium, resident macrophages preserved homeostasis, while recruited macrophages retained an inflammatory program. Following TAC, transcriptional profiles of recruited and resident macrophages remained distinct, with recruited macrophages driving immune responses and resident macrophages promoting tissue remodeling.
As we observed that the cardiac tissue environment can override macrophage ontogeny, we also demonstrated that both macrophage subsets actively modify their tissue surroundings. This is evidenced by changes in cardiac function upon selective depletion of macrophage subsets during injury. Depleting recruited macrophages reduced overall macrophages numbers and improved cardiac function after I/R injury. Conversely, depleting resident macrophages disrupted wound healing, worsening cardiac dysfunction. These findings demonstrate that macrophages directly influence cardiomyocytes, fibroblasts, and other cardiac cell types, profoundly altering the cardiac microenvironment and contributing to functional outcomes post-injury.
Conclusion:
Ischemic and non-ischemic cardiac injuries trigger a transient surge in monocyte recruitment and macrophage differentiation, with recruited macrophages progressively integrating into the tissue-resident pool at different paces. The injury type dictates distinct macrophage trajectories and transcriptomic programs, and especially in the infarcted tissue, converges on a common outcome of remodeling that can predispose to heart failure if unresolved. Modulating the balance between macrophage subsets affects functional recovery, highlighting macrophage plasticity as a potential therapeutic target to mitigate adverse remodeling.
