The Dual Role of Macrophages in MIRI and MI by Immunity and Inflammation: Damage, Repair, Crosstalk, and Therapy

The global prevalence of coronary artery disease (CAD) continues to escalate globally. A substantial proportion of CAD patients develop myocardial ischemic injury or myocardial infarction (MI), while reperfusion therapy paradoxically induces myocardial ischemia/reperfusion injury (MIRI). Tissue‐resident and recruited macrophages critically orchestrate cardiac inflammation resolution and repair‐remodeling processes. Pathogenically, MIRI features early explosive inflammation with secondary reperfusion injury, whereas MI progresses from acute inflammation to reparative fibrosis. We highlight two pivotal macrophage subsets—C─C chemokine receptor type 2 (CCR2) high macrophages dominating early MI phases and triggering receptor expressed on myeloid cells 2 (TREM2) high macrophages prevailing in late stages—exploring their distinct roles in both MI and MIRI. This includes examining macrophage crosstalk with neutrophils and other immune‐inflammatory cells. Finally, we discuss macrophage‐targeted therapies encompassing anti‐inflammatory modulation, exosome‐mediated delivery, and stem cell interventions to mitigate cardiac injury progression.