Kaori Endo-Umeda1, Eunyoung Kim1,2,3, David G Thomas1,4, Wenli Liu1, Huijuan Dou1, Mustafa Yalcinkaya1, Sandra Abramowicz1, Tong Xiao1, Per Antonson5, Jan-Åke Gustafsson5,6, Makoto Makishima3, Muredach P Reilly2, Nan Wang1, Alan R Tall1. 1. Division of Molecular Medicine (K.E.-U., E.K., D.G.T., W.L., H.D., M.Y., S.A., T.X., N.W., A.R.T.), Department of Medicine, Columbia University, NY. 2. Division of Cardiology (E.K., M.P.R.), Department of Medicine, Columbia University, NY. 3. Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan (K.E.-U., M.M.). 4. Now with Department of Medicine, New York Presbyterian Hospital/Weill Cornell Medicine (D.G.T.). 5. Department of Biosciences and Nutrition, Karolinska Institute, Sweden (P.A., J.-Å.G.). 6. Center for Nuclear Receptors and Cell Signaling, University of Houston, TX (J.-Å.G.).
Abstract
BACKGROUND: Cholesterol loaded macrophage foam cells are a prominent feature of atherosclerotic plaques. Single-cell RNA sequencing has identified foam cells as TREM2 (triggering receptor expressed on myeloid cells 2) positive populations with low expression of inflammatory genes, resembling the TREM2 positive microglia of neurodegenerative diseases. Cholesterol loading of macrophages in vitro results in activation of LXR (liver X receptor) transcription factors and suppression of inflammatory genes. METHODS: To test the hypothesis that LXRs mediate anti-inflammatory effects in Trem2 expressing atherosclerotic plaque foam cells, we performed RNA profiling on plaque cells from hypercholesterolemic mice with myeloid LXR deficiency. RESULTS: Myeloid LXR deficiency led to a dramatic increase in atherosclerosis with increased monocyte entry, foam cell formation, and plaque inflammation. Bulk cell-RNA profiling of plaque myeloid cells showed prominent upregulation of inflammatory mediators including oxidative, chemokine, and chemotactic genes. Single-cell RNA sequencing revealed increased numbers of foamy TREM2-expressing macrophages; however, these cells had reduced expression of the Trem2 gene expression module, including phagocytic and cholesterol efflux genes, and had switched to a proinflammatory and proliferative phenotype. Expression of Trem2 was suppressed by inflammatory signals but not directly affected by LXR activation in bone marrow-derived macrophages. CONCLUSIONS: Our current studies reveal the key role of macrophage LXRs in promoting the Trem2 gene expression program and in suppressing inflammation in foam cells of atherosclerotic plaques.
BACKGROUND: Cholesterol loaded macrophage foam cells are a prominent feature of atherosclerotic plaques. Single-cell RNA sequencing has identified foam cells as TREM2 (triggering receptor expressed on myeloid cells 2) positive populations with low expression of inflammatory genes, resembling the TREM2 positive microglia of neurodegenerative diseases. Cholesterol loading of macrophages in vitro results in activation of LXR (liver X receptor) transcription factors and suppression of inflammatory genes. METHODS: To test the hypothesis that LXRs mediate anti-inflammatory effects in Trem2 expressing atherosclerotic plaque foam cells, we performed RNA profiling on plaque cells from hypercholesterolemic mice with myeloid LXR deficiency. RESULTS: Myeloid LXR deficiency led to a dramatic increase in atherosclerosis with increased monocyte entry, foam cell formation, and plaque inflammation. Bulk cell-RNA profiling of plaque myeloid cells showed prominent upregulation of inflammatory mediators including oxidative, chemokine, and chemotactic genes. Single-cell RNA sequencing revealed increased numbers of foamy TREM2-expressing macrophages; however, these cells had reduced expression of the Trem2 gene expression module, including phagocytic and cholesterol efflux genes, and had switched to a proinflammatory and proliferative phenotype. Expression of Trem2 was suppressed by inflammatory signals but not directly affected by LXR activation in bone marrow-derived macrophages. CONCLUSIONS: Our current studies reveal the key role of macrophage LXRs in promoting the Trem2 gene expression program and in suppressing inflammation in foam cells of atherosclerotic plaques.
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