[Dual role and therapeutic potential of TREM2 in atherosclerosis]

Triggering receptor expressed on myeloid cells 2 (TREM2) is a key transmembrane immune receptor that is specifically highly expressed in myeloid cells, particularly macrophages, within atherosclerosis (AS) plaques. Advances in single-cell sequencing technology have clearly defined TREM2-high macrophages as a distinct subpopulation known as lipid-associated macrophages. TREM2 exhibits stage-specific bidirectional regulatory effects during the progression of AS. In the early stage of the disease, TREM2 promotes cholesterol uptake by upregulating the scavenger receptor CD36, thereby accelerating foam cell formation and lesion expansion. In the advanced stage, however, its protective effects become prominent: TREM2 enhances macrophage survival, drives reverse cholesterol transport, and improves efferocytosis efficiency, thereby effectively inhibiting necrotic core expansion and maintaining plaque stability. At the molecular level, the TREM2-DAP12 complex upregulates CD36-mediated lipid uptake through the p38 mitogen-activated protein kinase/peroxisome proliferator-activated receptor gamma (PPARγ) axis, whereas deficiency of liver X receptor (LXR) can weaken its protective effects. Mitochondrial reactive oxygen species (mtROS) drive the transition of macrophages toward a pro-inflammatory foam cell phenotype through signal transducer and activator of transcription 5 (STAT5). In addition, ferroptosis-related mitochondrial dysfunction promotes the death of advanced foam macrophages and aggravates plaque instability. In terms of clinical translation, soluble TREM2 (sTREM2) levels are associated with the risk of coronary heart disease and adverse cardiovascular events, suggesting that sTREM2 may serve as a potential biomarker reflecting plaque inflammation and cellular injury and may provide incremental predictive value beyond high-sensitivity C-reactive protein. TREM2 agonists, such as AL002a, can reprogram foam macrophages and enhance efferocytosis and necrotic core clearance, thereby improving plaque stability and showing potential for precision intervention. In summary, TREM2 shows a "double-edged sword" role at different stages of AS, and precise stage-specific modulation of TREM2 may represent a new direction for immunotherapy in AS.