Myocardial infarction and the immune response - Scarring or regeneration? A comparative look at mammals and popular regenerating animal models

It has been well established that the survival and long-term outcome for patients suffering a myocardial infarction in part depends on the resulting immune response to injury. These processes are complex, and a clear path to useful immunotherapies for the treatment of cardiovascular damage in humans remains elusive. Mammals hold a great potential for repair of cardiac tissue during fetal and early neonatal life, an ability that is lost in the adult, coinciding with a maturation of the immune system. Unlike mammals, the axolotl and zebrafish, which are popular model organisms in regenerative medicine, successfully recover functionally and anatomically following infarction injury. In this review, we present an in-depth comparative look at the immune response to cardiac infarction damage in adult and fetal/early neonatal mammals as well as axolotls and zebrafish, with an emphasis on the role of macrophages. This current knowledge is instrumental for transferring new findings in regenerative animal models to the development of novel immune-modulating treatments. These could improve the rate of survival and quality of life after injury for the millions of people suffering from a myocardial infarction every year. The regenerative process in axolotls and zebrafish has been found to rely on the actions of key immune cells. Macrophages in particular are essential to cardiac regeneration in axolotls and zebrafish as well as mammalian fetuses and neonates. There is great interest in the heterogeneity of macrophage populations, as mammalian embryonic macrophages appear to be facilitators of regeneration, while monocyte-derived macrophages in adults chiefly promote fibrosis. Monocyte derived macrophages also exist in a spectrum of phenotypes grossly divided into pro-inflammatory M1 and immune-resolving M2 cells, with divergent roles following tissue damage. The phenotypes of axolotl macrophages remain uncharacterized, but early studies suggest that the macrophages recruited to the infarction site are primarily similar to embryonic or M2-type macrophages. Findings in animal models as well as humans, indicates that the inflammatory response and especially the action of macrophages should be examined further, which requires a detailed understanding of these processes in models both capable and incapable of cardiac regeneration. Immunotherapies aimed at improving outcomes in mammals, should not eliminate the inflammatory response, but rather modulate it to resemble that of competent regenerators.