Interleukin 17 Drives Vascular Inflammation, Endothelial Dysfunction, and Arterial Hypertension in Psoriasis-Like Skin Disease
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Published:2014-12
Issue:12
Volume:34
Page:2658-2668
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ISSN:1079-5642
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Container-title:Arteriosclerosis, Thrombosis, and Vascular Biology
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language:en
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Short-container-title:ATVB
Author:
Karbach Susanne1, Croxford Andrew L.1, Oelze Matthias1, Schüler Rebecca1, Minwegen Daniel1, Wegner Joanna1, Koukes Lija1, Yogev Nir1, Nikolaev Alexei1, Reißig Sonja1, Ullmann Alexander1, Knorr Maike1, Waldner Maximilian1, Neurath Markus F.1, Li Huige1, Wu Zhixiong1, Brochhausen Christoph1, Scheller Jürgen1, Rose-John Stefan1, Piotrowski Carolin1, Bechmann Ingo1, Radsak Markus1, Wild Philipp1, Daiber Andreas1, von Stebut Esther1, Wenzel Philip1, Waisman Ari1, Münzel Thomas1
Affiliation:
1. From the Institute for Molecular Medicine (S.K., A.L.C., R.S., N.Y., A.N., S.R., A.W.), Department of Medicine 2 (S.K., M.O., D.M., M.K., P. Wild, A.D., P. Wenzel, T.M.), Department of Dermatology (J.W., L.K., E.v.S.), Department of Pharmacology (H.L., Z.W.), Institute for Pathology (C.B.), Center for Thrombosis and Hemostasis (P. Wild, P. Wenzel, T.M.), German Center for Cardiovascular Research (DZHK), partner site RhineMain (A.U., P.W.), and Department of Medicine 3 (M.R.), University Medical...
Abstract
Objective—
Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease.
Approach and Results—
Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A
ind/+
mice), associated with increased reactive oxygen species formation and circulating CD11b
+
inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A
ind/+
mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase
+
CD11b
+
GR1
+
F4/80
−
cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-α and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17A
ind/+
mice.
Conclusions—
Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase
+
CD11b
+
GR1
+
F4/80
−
inflammatory cells. Depletion of the GR-1
+
immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17A
ind/+
mice.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
190 articles.
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