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

作者：Tiit Örd, Senthil Palani, Judith Giroud Gerbetant, Susanna Bodoy, Tapio Lönnberg, Henri Niskanen, Aarthi Ravindran, Lari Holappa, Melody Chemaly, Mari Taipale, Kadri Õunap, Retu Haikonen, Husain A. Talukdar, Katyayani Sukhavasi, Heidi Liljenbäck, Jenni Virta, Anna‐Kaisa Ruotsalainen, Clara Pierrot-Blanchet, Maxwell W. G. Miner, Olli Moisio, Noora Rajala, Xiang‐Guo Li, Philip S. Low, Antti Saraste, Merja Heinäniemi, Seppo Ylä‐Herttuala, Johan Björkegren, Ulf Hedin, Ljubica Matic, Laurent Yvan‐Charvet, Manuel Palacı́n, Anne Roivainen, Minna U. Kaikkonen · 发表于：Cardiovascular Research · 年份：2025 · DOI：10.1093/cvr/cvaf210 · 被引用次数：9 · 研究领域：Immune cells in cancer、Single-cell and spatial transcriptomics、Atherosclerosis and Cardiovascular Diseases

AIMS: 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. METHODS AND RESULTS: We used single-cell RNA sequencing (scRNA-seq) and translating ribosome affinity purification sequencing (TRAP-seq) to profile macrophage-specific gene programmes in a mouse model of atherosclerosis across the aorta, adipose tissue, and liver. Our data highlight tissue-specific macrophage gene programmes and identify markers that are shared across mouse and human plaques. First, we identified soluble Trem2 as a potential circulating biomarker for differentiating between asymptomatic and symptomatic individuals. Secondly, we leveraged the pronounced expression of Folr2 and Slc7a7 to explore the potential of folate and glutamine as positron emission tomography (PET) tracers for disease burden assessment through in vivo PET imaging. Finally, we show that knockout of Slc7a7 inhibits acetylated low-density lipoprotein uptake and dampens the gene signature linked to lipid-associated macrophages. This suggests that glutamine signalling may play a critical role in foam cell formation, a key event in atherosclerosis. CONCLUSION: Our findings provide novel insights into macrophage-specific gene programmes ...