TREM2 signaling in cardiovascular disease: macrophage heterogeneity, timing, and therapeutic opportunity.

BACKGROUND: Cardiovascular diseases remain the leading cause of global morbidity and mortality, with pathogenesis extending beyond hemodynamic derangements to involve chronic, maladaptive immune-metabolic crosstalk. Macrophage functional identity has evolved beyond the M1/M2 paradigm toward a model of high heterogeneity and dynamic plasticity, wherein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) serves as a pivotal molecular hub. AIM OF REVIEW: This review systematically delineates the spatiotemporal dynamics and functional duality of TREM2+ macrophages across major cardiovascular conditions, including atherosclerosis, myocardial infarction, heart failure and sepsis-induced cardiomyopathy. It further evaluates the current evidence and limitations of soluble TREM2 (sTREM2) as a candidate biomarker and critically appraises translational strategies targeting this pathway. KEY SCIENTIFIC CONCEPTS OF REVIEW: TREM2 integrates lipid sensing, efferocytosis, metabolic reprogramming, and immune modulation to exert highly context-dependent effects. In early disease stages, TREM2+ macrophages participate in lipid accumulation and inflammation initiation, whereas in later phases, they contribute to plaque stabilization, tissue repair coordination and microenvironmental homeostasis. sTREM2 may serve as a dynamic indicator of macrophage activation and functional transition, but its clinical utility for risk stratification and therapeutic monitoring remains investigational. Translational approaches include agonistic antibodies, small-molecule agonists, gene/RNA-based therapies, and localized delivery systems. However, clinical progress is challenged by profound context dependency, sexual dimorphism, undefined therapeutic windows, and the absence of cardiovascular-specific clinical validation. Future advancement requires integrating multiomics technologies, biomarker-guided trials, and systems biology to move TREM2 from mechanistic insight toward precision cardiovascular immunomodulation.