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Published on: December 17, 2019
TREM2 signaling in cardiovascular disease: macrophage heterogeneity, timing, and therapeutic opportunity
Ke Yang1, Xuefang Ma1, Binyan Wang1
1State Key Laboratory of Component-based Chinese Medicine & Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae for the Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
Insights
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a dual role in cardiovascular diseases, influencing inflammation and repair. Soluble TREM2 (sTREM2) shows potential as a biomarker, but therapeutic targeting requires further research.
Area of Science:
- Immunology
- Cardiovascular Biology
- Molecular Medicine
Background:
- Cardiovascular diseases (CVDs) are a leading cause of death, driven by complex immune-metabolic interactions.
- Macrophage function is highly heterogeneous and plastic, with Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a key regulator.
- TREM2 integrates lipid sensing, efferocytosis, metabolism, and immune responses in a context-dependent manner.
Purpose of the Study:
- To review the dynamic roles of TREM2-expressing macrophages in atherosclerosis, myocardial infarction, heart failure, and sepsis-induced cardiomyopathy.
- To evaluate soluble TREM2 (sTREM2) as a potential biomarker for CVDs.
- To critically assess therapeutic strategies targeting the TREM2 pathway in cardiovascular conditions.
Main Methods:
- Systematic review of literature on TREM2 function in cardiovascular diseases.
- Analysis of TREM2's spatiotemporal dynamics and functional duality.
- Evaluation of current evidence for sTREM2 as a biomarker and translational approaches.
Main Results:
- TREM2+ macrophages exhibit context-dependent effects, promoting inflammation in early stages and tissue repair in later stages.
- sTREM2 may reflect macrophage activation but requires further validation for clinical utility in risk stratification and therapy monitoring.
- Translational strategies include antibodies, agonists, and gene therapies, but face challenges like context dependency and lack of cardiovascular-specific validation.
Conclusions:
- TREM2 is a critical mediator in cardiovascular pathophysiology, with distinct roles in different disease phases.
- Targeting TREM2 presents therapeutic potential but requires overcoming significant challenges for clinical application.
- Future research should integrate multiomics and systems biology for precision cardiovascular immunomodulation via TREM2.
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.
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