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.