TREM2 in the Development of Atherosclerosis

TREM2 is most studied in the context of Alzheimer's disease and related forms of neurodegeneration, where it seems to affect inflammation driven by microglia and loss of the ability of microglia to clear amyloid-β from the aging brain. Microglia are, more or less, the central nervous system version of the innate immune cells called macrophages that are found throughout the rest of the body. Atherosclerosis is the largest cause of human mortality, and is driven by macrophage dysfunction. Macrophages are responsible for clearing excess lipids from blood vessel walls, but when these cells become overwhelmed by local excesses of lipids they become inflammatory, contributing to the growth of atherosclerotic plaques rather than helping the situation. As noted here, it appears that TREM2 is involved in this process, affecting the capacity of macrophages to resist the plaque environment.

Atherosclerosis is driven by the expansion of cholesterol-loaded 'foamy' macrophages in the arterial intima. Factors regulating foamy macrophage differentiation and survival in plaque remain poorly understood. Here we show, using trajectory analysis of integrated single-cell RNA sequencing data and a genome-wide CRISPR screen, that triggering receptor expressed on myeloid cells 2 (Trem2) is associated with foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up oxidized low-density lipoprotein (oxLDL). Myeloid-specific deletion of Trem2 showed an attenuation of plaque progression, even when targeted in established atherosclerotic lesions, and was independent of changes in circulating cytokines, monocyte recruitment, or cholesterol levels.

Mechanistically, we link Trem2-deficient macrophages with a failure to upregulate cholesterol efflux molecules, resulting in impaired proliferation and survival. Overall, we identify Trem2 as a regulator of foamy macrophage differentiation and atherosclerotic plaque growth and as a putative therapeutic target for atherosclerosis.


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