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Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease

Arteriosclerosis, thrombosis, and vascular biology. Bd. 34. H. 12. Hagerstown, Md.: Lippincott, Williams & Wikins 2014 S. 2658 - 2668

Erscheinungsjahr: 2014

ISBN/ISSN: 1079-5642 ; 1524-4636

Publikationstyp: Zeitschriftenaufsatz

Sprache: Englisch

Doi/URN: 10.1161/ATVBAHA.114.304108

Volltext über DOI/URN

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Inhaltszusammenfassung


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/+) mi...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-alpha 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.» weiterlesen» einklappen

Autoren


Karbach, Susanne (Autor)
Croxford, Andrew L. (Autor)
Oelze, Matthias (Autor)
Schüler, Rebecca (Autor)
Minwegen, Daniel (Autor)
Wegner, Joanna (Autor)
Koukes, Lija (Autor)
Yogev, Nir (Autor)
Nikolaev, Alexei (Autor)
Reißig, Sonja (Autor)
Ullmann, Alexander (Autor)
Knorr, Maike (Autor)
Waldner, Maximilian (Autor)
Neurath, Markus F. (Autor)
Li, Huige (Autor)
Wu, Zhixiong (Autor)
Brochhausen, Christoph (Autor)
Scheller, Jürgen (Autor)
Rose-John, Stefan (Autor)
Piotrowski, Carolin (Autor)
Bechmann, Ingo (Autor)
Radsak, Markus (Autor)
Wild, Philipp (Autor)
Daiber, Andreas (Autor)
Stebut, Esther von (Autor)
Wenzel, Philip (Autor)
Waisman, Ari (Autor)
Münzel, Thomas (Autor)

Klassifikation


DDC Sachgruppe:
Medizin