Foamy macrophages in atherosclerosis: unraveling the balance between pro- and anti-inflammatory roles in disease progression

Abstract

Atherosclerosis is a complex immuno-metabolic disease characterized by lipid accumulation and chronic inflammation within arterial walls, leading to cardiovascular events such as stroke and myocardial infarction. Central to the disease are arterial plaques initiated by modified low-density lipoproteins (LDL), particularly oxidized LDL, deposited in the arterial intima. This deposition activates tissue-resident macrophages (TRMs), inducing a lipid-loaded "foamy" phenotype. Additionally, endothelial dysfunction promotes monocyte recruitment, differentiation into macrophages, and further foam cell formation. Foamy macrophages were initially identified as anti-inflammatory but have recently shown dual functionality, possibly depending on the disease stage and phenotype. Recent mouse and human studies also identified subsets of "foamy" macrophages with both pro and anti-inflammatory features. This review examines "foamy" macrophage complex roles and phenotypic diversity in atherosclerosis, emphasizing their potential as therapeutic targets to reduce inflammation and slow disease progression.

Keywords: Olfr2; TREM2; atherosclerosis; foamy; inflammation; macrophages.

Figure 1

Foamy macrophages possible origin from distinct aortic macrophage subsets based on specific marker genes. Schematic overview illustrating how multiple macrophage subsets, including resident macrophages, TREM2-expressing macrophages, interferon-inducible macrophages, inflammatory macrophages, and smooth muscle cells–derived macrophages, may each give rise to foamy macrophages. Key publications defining various subsets of macrophages based on specific marker genes are shown, highlighting the known and potential transitions (indicated by?) that may lead to lipid accumulation and the “foamy” phenotype.

Figure 2

Drivers of foamy macrophage function and phenotype in atherosclerosis. Schematic representation of distinct macrophage foamy phenotypes within the atherosclerotic plaque environment. The anti-inflammatory foamy phenotype (left, blue) maintains controlled cholesterol accumulation, efficient cholesterol export, and reduced inflammatory signaling particularly IL-1β through increasing the expression of IL-1R2 (a decoy receptor) as well as having a dampening effect on NF-κB pathway, and maintaining higher anti-inflammatory gene signature especially IL10 contributing to plaque stability. The anti-inflammatory phenotype is also proposed to have a higher TREM2 expression and lower TREM1 expression contributing to the anti-inflammatory gene signature. In contrast, the pro-inflammatory foamy phenotype (right, pink) is marked by excessive cholesterol accumulation, dysregulated cholesterol export, and heightened production of inflammatory mediators like IL-1β and other inflammatory mediators like iNOS due to activation of NF-κB pathway and reduced expression of TREM2, promoting plaque progression and necrotic core formation. Key molecular pathways (e.g., NF-κB, LXR, TREM2, Olfr2) are highlighted, illustrating how foamy macrophage polarization and the interplay between these pathways can influence atherosclerotic lesion outcomes.