Interleukin 17 Drives Vascular Inflammation, Endothelial Dysfunction, and Arterial Hypertension in Psoriasis-Like Skin Disease

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.

Immune Mechanisms in Arterial Hypertension

“…Dermal overexpression of IL-17A induces not only psoriasis-like lesions but also endothelial dysfunction, vascular oxidative stress, and arterial hypertension. 51 The importance of IL-17 in hypertension is supported by studies of IL-6-deficient mice. IL-6 is needed for polarization of T H 17 cells, and mice lacking this cytokine have lower BP and less endothelial dysfunction in response to Ang II infusion.…”

Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

“…Res. ); hypertension in rat [22] and mouse [23,27]; sepsis in rat [45,46]; psoriasis in mouse [47]; congestive heart failure and alcohol cardiomyopathy in mouse [48]; aging process in mice [49]. We also applied DHE staining in various cell culture systems: hyperglycemic endothelial cells [50]; acetaldehyde challenged cardiomyocytes [51]; oxidative burst in phorbol ester stimulated human neutrophils [52].…”

“…Redox Biology 12 (2017) [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] meaning and can be used in combination with state-of-the-art assays or accepted redox biomarkers (Fig. 4).…”

IL-6 Trans-Signaling Drives Murine Crescentic GN

“…Bioactivity against IL-6 in vivo of this antibody and the batch used was evidenced previously by us and others. 4,27,28 Selective Inhibition of Trans-Signaling Improves the Course of NTN in BALB/c Mice Next we assessed the effects of selective blockade of IL-6 transsignaling with sgp130Fc in NTN ( Figure 5, left panels). sgp130Fc injections started after disease induction, i.e., in a therapeutic manner and in an attempt to avoid interference with disease induction.…”