Hypertension and vascular alterations in lupus autoimmunity

Systemic lupus erythematosus (SLE), which is estimated to affect 30–50 people out of 100 000, is considered to be one of the most heterogeneous illnesses to treat [1]. This systemic autoimmune disease manifests itself through an array of symptoms that often include fever, skin rash and arthritis and can lead to lupus nephritis and nervous system disease in more severe cases [1]. This diversity amongst disease manifestations creates challenges for both diagnosis and treatment. As such, SLE patients, consisting predominantly of women of childbearing age, suffer from considerable comorbidities as a result of accumulated organ damage and are at increased risk of premature death from infection or cardiovascular events [2]. Cardiovascular diseases (CVD) are responsible for a quarter of SLE deaths, which has partly been attributed to accelerated atherosclerosis in these patients [3]. Hypertension, a known risk factor and predictor of future cardiovascular events, is highly prevalent amongst SLE patients. In one cohort, women with SLE were reported to be almost twice as likely to have high blood pressure (BP) compared with healthy subjects [4]. The increased levels of circulating inflammatory cytokines and autoantibodies typical of lupus autoimmunity have been implicated in hypertension in SLE [1,5]; however, the pathogenesis of hypertension in SLE is incompletely understood. Various murine models of lupus have been developed to better understand disease progression and comorbidities. Although most models develop hallmark characteristics of SLE such as immunity modulation and renal involvement, development of hypertension has only been reported in NZBWF1 mice, a spontaneous model of lupus. These mice showed impairment of renal hemodynamic and excretory function and vascular endothelial dysfunction which were both associated with the progression of hypertension [5]. In this issue of the Journal of Hypertension, Robles-Vera et al.[6] shed light on the impact of Toll-like receptor-7 (TLR7)-driven lupus autoimmunity on BP, and its association with oxidative stress and IL-17. TLR7 is an endosomal membrane protein whose activation triggers cytokine release and type I interferon production [7]. In this model, female Bagg albino/c (BALB/c) mice were subjected to a topical application of imiquimod (IMQ), a TLR7 agonist which induced lupus-like autoimmunity including elevated levels of autoantibodies and inflammatory cytokines, splenomegaly, and immune complex glomerulonephritis. In addition, a progressive increase in SBP was observed. Increases in BP were accompanied by vascular alterations: media thickness was significantly increased and associated with reduced lumen diameter and a 40% increase in media/lumen ratio. ROS (reactive oxygen species) production and expression of vascular adhesion molecules and proinflammatory cytokines were also increased in the arteries of IMQ-treated mice, suggesting an increase in vascular oxidative stress and inflammation in this model. NADPH oxidase activity and BP were both reduced following administration of an IL-17 neutralizing antibody. The authors conclude that TLR7-mediated induction of IL-17 increases NADPH oxidase activity and promotes endothelial injury and development of hypertension. This conclusion was further underscored by the fact that coadministration of antioxidants [combination 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL) and apocynin] with IMQ reduced BP and improved vascular function. Significantly, while there was evidence of renal hypercellularity, immune deposits and albuminuria, the authors did not examine whether there was glomerular filtration rate decline. This could represent an additional mechanism for elevated BP in these animals. There is mounting evidence to support a role for IL17-producing CD4+ T cells (Th17) in hypertension development and maintenance. Th17 cells, known to drive autoimmune disease progression and organ damage [8,9], have recently been identified to be key players in hypertension [10]. Through the release of IL-17, Th17 cells have been shown to exacerbate rises in BP by mediating endothelial dysfunction and renal injury. More specifically, IL-17 was shown to act through the activation of RhoA/Rho-kinase and inhibitory phosphorylation of endothelial nitric oxide synthase, resulting in reduced NO-dependent vasorelaxation responses in mice [11]. Neutralization of IL-17 and inhibition of Rho-kinase both prevented the rise in BP by restoring NO production. Similarly, IL-17 deficient mice were protected from angiotensin II-mediated vascular injury and hypertension, which was associated with reduced angiotensin II-induced ROS production [12]. The current article extends this work to show a critical role of IL-17 in development of hypertension in murine SLE. Consistent with previous literature this effect seems to involve induction of ROS production and impairment in nitric oxide signaling. In summary, Robles-Vera et al. have established a novel model of TLR7-dependent SLE with development of hypertension. Using this model they provide new evidence implicating IL-17-mediated ROS production in the development of vascular dysfunction and hypertension in SLE. While further studies are needed to fully understand the development of hypertension in SLE, the current study significantly advances our understanding of the molecular determinants of hypertension in lupus, which is crucial to developing preventive measures and treatments to reduce the incidence of CVD morbidity and mortality in SLE. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

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