TREM2 signaling in cardiovascular disease: macrophage heterogeneity, timing, and therapeutic opportunity.
TL;DR
This review systematically delineates the spatiotemporal dynamics and functional duality of TREM2+ macrophages across major cardiovascular conditions, and further evaluates the current evidence and limitations of soluble TREM2 (sTREM2) as a candidate biomarker and critically appraises translational strategies targeting this pathway.
Abstract
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.