Good cop, bad cop? Rethinking the roles of cardiac macrophages in injury.

Cardiac macrophages (CMs) preserve homeostasis in the heart by clearing cellular debris and facilitating electrical conduction. During tissue injury, embryonically derived CMs (em-CMs) have traditionally been deemed beneficial for promoting tissue repair, whereas monocyte-derived CMs (mo-CMs) are considered detrimental, contributing to inflammation and tissue damage. However, Kasam et al. challenge this binary classification using cardiac-specific strategies to expand either em-CM or mo-CM populations. As expected, mice with cardiac-specific mo-CM expansion exhibited adverse outcomes following transverse aortic constriction (TAC). Surprisingly, mice with expanded em-CMs also showed a marked decline in cardiac function after TAC, which was associated with an unexpected interaction with mo-CMs. This deterioration was temporally regulated, occurring only if em-CMs were expanded before TAC induction. Together, these findings suggest that simplistic classification of CMs as either beneficial or harmful underestimates their complex roles in cardiac pathology, highlighting the need to reassess current views of macrophage function in heart injury.