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
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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
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Medizin
