title: IL-17A influences essential functions of the monocyte/macrophage lineage and is involved in advanced murine and human atherosclerosis.
abstract: Atherosclerosis is a chronic inflammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. IL-17A is a proinflammatory cytokine, which modulates immune cell trafficking and is involved inflammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study, we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. The 26-wk-old apolipoprotein E-deficient mice were fed a standard chow diet and treated either with IL-17A mAb (n = 15) or irrelevant Ig (n = 10) for 16 wk. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progression (p = 0.001) by reducing inflammatory burden and cellular infiltration (p = 0.01) and improved lesion stability (p = 0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, and sensitization of APCs toward pathogen-derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a proinflammatory milieu and upregulation of molecules expressed by the IL-17A-induced macrophage subtype. In this study, we show that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces plaque stabilization in advanced lesions in apolipoprotein E-deficient mice. The underlying mechanisms involve reduced inflammation and distinct effects of IL-17A on monocyte/macrophage lineage. In addition, translational experiments underline the relevance for the human system.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany; Christian.Erbel@med.uni-heidelberg.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Erbel
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Mohammadreza
authors.initials: M
authors.lastname: Akhavanpoor
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Deniz
authors.initials: D
authors.lastname: Okuyucu
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Susanne
authors.initials: S
authors.lastname: Wangler
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Alex
authors.initials: A
authors.lastname: Dietz
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Institute of Cardiovascular Regeneration, University of Frankfurt am Main, Frankfurt am Main 60590, Germany;
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Stellos
authors.affiliation: Illumina, Inc., San Diego, CA 92122;
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Little
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Doesch
authors.affiliation: Department of Vascular Surgery, University of Heidelberg, Heidelberg 69120, Germany; Department of Endovascular Surgery, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Maani
authors.initials: M
authors.lastname: Hakimi
authors.affiliation: Department of Cardiology, SLK-Hospital Heilbronn, Bad Friedrichshall 74177, Germany;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Dengler
authors.affiliation: Institute of Immunology, University of Heidelberg, Heidelberg 69120, Germany; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Erwin
authors.initials: E
authors.lastname: Blessing
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany; German Centre for Cardiovascular Research, Partner Site, Heidelberg 69120, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg 69120, Germany;
authors.forename: Christian A
authors.initials: CA
authors.lastname: Gleissner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation; D016000:Cluster Analysis; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005487:Foam Cells / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D050356:Lipid Metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010973:Platelet Adhesiveness / Q000187:drug effects; D059467:Transcriptome
chemical_list: D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D020381:Interleukin-17