TREM2 protects from atherosclerosis by limiting necrotic core formation

Abstract

Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, and its main complications—myocardial infarction and stroke—are the leading cause of mortality worldwide1,2. Recent studies have identified triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating myeloid cell functions3, to be highly expressed in macrophage foam cells in experimental and human atherosclerosis4. However, the role of TREM2 in atherosclerosis is not fully known. Here we show that hematopoietic or global TREM2 deficiency increased, whereas TREM2 agonism decreased, necrotic core formation in early atherosclerosis. We demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages and to the survival of lipid-laden macrophages, indicating a crucial role of TREM2 in maintaining the balance between foam cell death and clearance of dead cells in atherosclerotic lesions, thereby controlling plaque necrosis.

MACanalyzeR: scRNA-seq Analysis Tool Reveals PPARγHI Lipid-Associated Macrophages Facilitate Thermogenic Expansion in BAT

“…In line with the protective role of LAMs, several authors reported that following HFD, depletion TREM2 + LAM exacerbates WAT dysfunction and metabolic abnormalities (Jaitin et al, 2019). Remarkably, TREM2 + LAMs exert a protective role in other metabolically-stressed tissues such as the heart (Piollet et al, 2024;Zhang et al, 2023).…”

Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability—Brief Report

“…26 However, in advanced plaques, whole-body Trem2 deletion led to increased necrotic core formation due to impaired efferocytosis and excess cell death. 27 Overall, these data suggest that while inhibiting Trem2 during early lesion development may slow disease progression, promoting Trem2 signaling in advanced disease could impair necrotic core formation and plaque inflammation to promote stability.…”

“…This conclusion is further supported by a recent report investigating germline Trem2 deletion in advanced atherosclerotic plaques that found while Trem2 deletion had no effect on plaque size, Trem2deficient mice had larger necrotic cores. 27 It has been proposed that the effect of macrophage cell death on plaque outcomes depends on the stage of plaque development. 39,40 Thus, we hypothesize that while promoting foamy macrophage cell death by inhibiting Trem2 during early atheroma development may slow progression, agonizing Trem2 in advanced lesions may be more important to promote plaque stability.…”

“…Recent reports indicate that Trem2 deficiency impairs foamy macrophage survival through impaired cholesterol efflux 30 and exacerbates necrotic core formation. 27 Thus, we hypothesized that promoting Trem2 signaling in atherosclerosis could drive macrophage survival, decrease plaque necrotic core formation, and promote stable plaque phenotypes. To test this hypothesis, we treated atherogenic Ldlr −/− mice with a mouse surrogate Trem2 agonist antibody AL002a.…”

Infiltrating lipid-rich macrophage subpopulations identified as a regulator of increasing prostate size in human benign prostatic hyperplasia

“…TREM2 + cells have been shown to have beneficial properties in hepatic and renal tissue damage, but blockade of these cells restores anti-tumor immunity [58][59][60][61] . There is evidence for both pro-and anti-atherosclerotic properties of TREM2 33,62 , and it remains possible that lipid-loaded macrophages have a role in restraining inflammation via PPAR 63 . In the tumor microenvironment, lipid-loading in tumor-associated macrophages decreases phagocytosis and increases PD-L1 expression, resulting in an immunosuppressive environment for tumor growth 17 .…”