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

• DOI: 10.1161/atvbaha.124.320797
• Publication Date: 2024-05-02T09:00:41Z
• Authors: Michael T. Patterson; Yingzheng Xu; Hannah Hillman; Victoria Osinski; Patricia R. Schrank; Ainsley E. Kennedy; Fanta Barrow; Alisha Zhu; Samuel Tollison; Sia Shekhar; Ingunn M. Stromnes; Ilaria Tassi; Dick Wu; Xavier S. Revelo; Bryce A. Binstadt; Jesse W. Williams
• Keywords: Mice, Knockout; Male; 0303 health sciences; Membrane Glycoproteins; Basic Sciences; Cell Survival; Aortic Diseases; Atherosclerosis; Diet, High-Fat; Plaque, Atherosclerotic; Mice, Inbred C57BL; Disease Models, Animal; Mice; Necrosis; 03 medical and health sciences; Receptors, LDL; Animals; Receptors, Immunologic; Foam Cells; Cell Proliferation

BACKGROUND: Trem2 (triggering receptor on myeloid cells 2), a surface lipid receptor, is expressed foamy macrophages within atherosclerotic lesions and regulates cell survival, proliferation, anti-inflammatory responses. Studies examining the role of in atherosclerosis have shown that deletion leads to impaired macrophage uptake, cholesterol efflux. Thus, we tested hypothesis administration agonist antibody (AL002a) atherogenic mice would enhance survival decrease necrotic core formation improve plaque stability. METHODS: To model therapeutic intervention approach, atherosclerosis-prone (Ldlr [low-density lipoprotein receptor] −/− ) were fed high-fat diet for 8 weeks, then transitioned treatment with AL002a or isotype control an additional weeks while continuing diet. RESULTS: AL002a-treated had increased lesion size both aortic root whole mount aorta, which correlated expansion area. This was due proliferation plaques. Importantly, plaques from showed improved features stability, including smaller cores, fibrous caps, greater collagen deposition. Single-cell RNA sequencing aorta suspensions isotype- revealed agonism dramatically altered transcriptome. included upregulation oxidative phosphorylation expression genes. In vitro studies validated promoted oxidized low-density CONCLUSIONS: expands by promoting but improves stability rewiring function efflux