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J Immunol ; 193(9): 4344-55, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25261478

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.


Subject(s)
Atherosclerosis/immunology , Atherosclerosis/metabolism , Interleukin-17/metabolism , Macrophages/metabolism , Monocytes/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Aorta/drug effects , Aorta/immunology , Aorta/metabolism , Aorta/pathology , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Atherosclerosis/drug therapy , Atherosclerosis/genetics , Atherosclerosis/pathology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Adhesion/drug effects , Cell Differentiation , Cluster Analysis , Coculture Techniques , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Disease Progression , Foam Cells/pathology , Gene Expression Profiling , Humans , Inflammation Mediators/metabolism , Interleukin-17/antagonists & inhibitors , Interleukin-17/pharmacology , Lipid Metabolism , Macrophages/cytology , Macrophages/drug effects , Macrophages/immunology , Male , Mice , Mice, Knockout , Monocytes/cytology , Monocytes/drug effects , Monocytes/immunology , Plaque, Atherosclerotic/drug therapy , Plaque, Atherosclerotic/immunology , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/pathology , Platelet Adhesiveness/drug effects , Transcriptome
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