Single-cell to pre-clinical evaluation of Trem2, Folr2, and Slc7a7 as macrophage-associated biomarkers for atherosclerosis

Abstract

<p><b>Aims</b></p><p>Atherosclerosis is a major global health challenge, with limited diagnostic and therapeutic options. Macrophages drive disease progression, but their tissue-specific phenotypes and functions remain poorly defined. This study aims to elucidate macrophage-driven mechanisms by characterizing their functional diversity across key metabolic and vascular tissues.</p><p><b>Methods and Results</b></p><p>We used single-cell RNA sequencing (scRNA-seq) and Translating Ribosome Affinity Purification sequencing (TRAP-seq) to profile macrophage-specific gene programs in a mouse model of atherosclerosis across the aorta, adipose tissue, and liver. Our data highlights tissue-specific macrophage gene programs and identifies markers that are shared across mouse and human plaques. First, we identified soluble <em>Trem2</em> as a potential circulating biomarker for differentiating between asymptomatic and symptomatic individuals. Secondly, we leveraged the pronounced expression of <em>Folr2</em> and <em>Slc7a7</em> to explore the potential of folate and glutamine as PET tracers for disease burden assessment through <em>in vivo</em> positron emission tomography (PET) imaging. Finally, we show that knockout of <em>Slc7a7</em> inhibits acetylated low-density lipoprotein (AcLDL) uptake and dampens the gene signature linked to lipid-associated macrophages. This suggests that glutamine signaling may play a critical role in foam cell formation, a key event in atherosclerosis.</p><p><b>Conclusions</b></p><p>Our findings provide novel insights into macrophage-specific gene programs during atherosclerosis progression and identify a set of promising biomarkers that can serve as a resource for future studies. These findings could significantly contribute to improving the diagnosis, monitoring, and treatment of atherosclerosis.</p>