TREM2 encodes plaque macrophage plasticity to mediate atherosclerosis regression

Authors

Hillman, H., Stuttgen, G. M., Lee, S.-J., Patterson, M. T., Chang, M. D., Zhou, Y., Kennedy, A. E., Schrank, P. R., Mitha, O., Barrett, T. J., Colonna, M., Williams, J. W.

Abstract

Cholesterol lowering therapies stabilize atherosclerotic plaque and reduce ischemic events, but the molecular mechanisms governing plaque remodeling or regression remain poorly defined. The lipid sensor TREM2 is a key modulator of plaque-associated foam cell development and was upregulated by plaque macrophages in atherosclerosis regression. We examined macrophage- or monocyte-specific Trem2 deletion during regression in mice and found that TREM2 expression on plaque macrophages, not newly recruited monocytes, was required for plaque regression. Trem2 deletion impeded necrotic core resolution, leading us to interrogate the efferocytic capacity of TREM2+ cells during lipid lowering. An in vitro model of cholesterol-experienced ex-lipid associated macrophages (Ex-LAMs) demonstrated that prior lipid priming enhanced efferocytic ability after unloading lipids and maintained expression of lysosomal and cytoskeletal remodeling genes. Augmented TREM2 signaling through genetic models or agonist treatment accelerated efferocytic ability in vitro and plaque regression in vivo. Thus, we posit that a TREM2-dependent ExLAM programming drives atherosclerosis resolution and facilitates beneficial plaque remodeling through enhanced efferocytosis. Overall, targeting the TREM2 pathway may be a viable strategy for stabilizing atherosclerotic plaques in patients treated with aggressive cholesterol control.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 03 Nov 2026.

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