IL-17A influences essential functions of the monocyte/macrophage lineage and is involved in advanced murine and human atherosclerosis

  • 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.

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Metadaten
Author:Christian ErbelGND, Mohammadreza Akhavanpoor, Deniz Okuyucu, Susanne Wangler, Alex Dietz, Li Zhao, Konstantinos Stellos, Kristina M. Little, Felix Lasitschka, Andreas Doesch, Maani Hakimi, Thomas J. Dengler, Thomas Giese, Erwin Blessing, Hugo KatusORCiDGND, Christian A. Gleissner
URN:urn:nbn:de:hebis:30:3-371782
DOI:https://doi.org/10.4049/jimmunol.1400181
ISSN:1550-6606
ISSN:0022-1767
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/25261478
Parent Title (English):The journal of immunology
Publisher:American Association of Immunologists
Place of publication:Bethesda, Md.
Document Type:Article
Language:English
Date of Publication (online):2014/09/26
Date of first Publication:2014/09/26
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2015/03/22
Volume:193
Issue:9
Page Number:12
First Page:4344
Last Page:4355
Note:
This article is distributed under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles. http://www.jimmunol.org/site/misc/authorchoice.xhtml
HeBIS-PPN:368921441
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoDeutsches Urheberrecht