Recent literature underscores the significance of macrophages in cardiac repair and regeneration, extending far beyond their traditional inflammatory and phagocytic roles. Several subsets of macrophages have been identified, each with distinct phenotypes, functions, and interactions within the cardiac environment, illustrating the complexity and diversity of their roles. Their adaptive capabilities, notably their phenotypic switch from pro-inflammatory to anti-inflammatory and reparative states, are crucial in orchestrating a reparative response. Restorative macrophages promote angiogenesis while preventing excessive fibrosis or maladaptive remodelling in the outcome of ischemic injury. The balanced interaction between the different macrophage subsets, the other cardiac cells (cardiomyocytes, fibroblasts, and endothelial cells), and the extracellular matrix is critical in determining the outcome after cardiac injury. Two major types of macrophages, identified as CCR2+ and CCR2- (Bajpal et al, 2019) , are monocyte-derived and tissue-resident, respectively. The crosstalk between these subsets is essential to promote healing and stimulate angiogenesis and fibrosis inhibition. Distinct subsets such as TIM4+/TIMD4- (Dick, 2019) or MerTK+/MerTK- (DeBerge, 2017) have gained more attention.
The recent study of Shao et al. (2024) enriches our understanding of cardiac repair mechanisms. The authors shed light on the intricate role of Activating Transcription Factor 3 (ATF3). The GAS6-ATF3 axis regulates the fate of MerTK+ cardiac macrophages, influencing their survival and proliferation. The administration of GAS6 improves cardiac repair in an ATF3-dependent manner.
Finally, a growing body of evidence, including the current study on ATF3, highlights the transcription factor's role in modulating macrophage function and underscores the potential of targeted therapies. These could include microRNA-based approaches or manipulations of specific macrophage subsets for improved cardiac repair. For instance, studies by Bejerano et al. (2018), Deniset et al. (Immunity, 2019), and Borrego et al. (2022) illustrate, respectively, the potential of microRNA-based therapies, the role of Gata6+ pericardial cavity macrophages, and macrophage conditioning in cardiac healing or anti-fibrotic functions post-myocardial infarction.
In conclusion, the cumulative research on cardiac macrophages opens new avenues for therapeutic strategies to modulate these cells for optimal cardiac repair. Therefore, understanding the nuanced roles of different macrophage types and their interactions with other cardiac cells is pivotal in developing effective treatments.
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