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

Lookup NU author(s): Professor Konstantinos Stellos

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Abstract

Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. 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, trans-lational experiments underline the relevance for the human system.


Publication metadata

Author(s): Erbel C, Akhavanpoor M, Okuyucu D, Wangler S, Dietz A, Zhao L, Stellos K, Little KM, Lasitschka F, Doesch A, Hakimi M, Dengler TJ, Giese T, Blessing E, Katus HA, Gleissner CA

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2014

Volume: 193

Issue: 9

Pages: 4344-4355

Print publication date: 01/11/2014

Online publication date: 17/10/2014

Acceptance date: 19/08/2014

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists

URL: https://doi.org/10.4049/jimmunol.1400181

DOI: 10.4049/jimmunol.1400181

PubMed id: 25261478


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