title: TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis.
abstract: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses, but its significance in non-infectious diseases remains unclear. Here, we demonstrate that TREM-1 promotes cardiovascular disease by exacerbating atherosclerosis. TREM-1 is expressed in advanced human atheromas and is highly upregulated under dyslipidemic conditions on circulating and on lesion-infiltrating myeloid cells in the Apoe-/-mouse model. TREM-1 strongly contributes to high-fat, high-cholesterol diet (HFCD)-induced monocytosis and synergizes with HFCD serum-derived factors to promote pro-inflammatory cytokine responses and foam cell formation of human monocyte/macrophages. Trem1-/-Apoe-/-mice exhibit substantially attenuated diet-induced atherogenesis. In particular, our results identify skewed monocyte differentiation and enhanced lipid accumulation as novel mechanisms through which TREM-1 can promote atherosclerosis. Collectively, our findings illustrate that dyslipidemia induces TREM-1 surface expression on myeloid cells and subsequently synergizes with TREM-1 to enhance monopoiesis, pro-atherogenic cytokine production and foam cell formation.
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zysset
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weber
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rihs
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brasseit
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Stefan
authors.identifier: 0000-0003-4438-7828
authors.initials: S
authors.lastname: Freigang
authors.affiliation: Department of Clinical Research, Tumor Immunology, University of Bern, CH-3008 Bern, Switzerland.|Department of Medical Oncology, Inselspital, University Hospital and University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Carsten
authors.identifier: 0000-0001-7512-513X
authors.initials: C
authors.lastname: Riether
authors.affiliation: Division of Clinical Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Yara
authors.initials: Y
authors.lastname: Banz
authors.affiliation: Innate Immunity Group, German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Cerwenka
authors.affiliation: Department of Clinical Research, Tumor Immunology, University of Bern, CH-3008 Bern, Switzerland.|Interfaculty Bioinformatics Unit and SIB Swiss Institute of Bioinformatics, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Cedric
authors.initials: C
authors.lastname: Simillion
authors.affiliation: Department of Internal Medicine, Internal Medicine, Lausanne University Hospital, CH-1011 Lausanne, Switzerland.
authors.forename: Pedro
authors.initials: P
authors.lastname: Marques-Vidal
authors.affiliation: Department of Clinical Research, Tumor Immunology, University of Bern, CH-3008 Bern, Switzerland.|Department of Medical Oncology, Inselspital, University Hospital and University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Ochsenbein
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Leslie
authors.initials: L
authors.lastname: Saurer
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mueller
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D001011:Aorta / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D002784:Cholesterol / Q000008:administration & dosage; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D005487:Foam Cells / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D050356:Lipid Metabolism / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D000073871:Triggering Receptor Expressed on Myeloid Cells-1 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology
chemical_list: D000950:Antigens, Ly; D001057:Apolipoproteins E; D016207:Cytokines; C494192:Ly-6C antigen, mouse; C408842:TREM1 protein, human; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D002784:Cholesterol