Inhibition of Interleukin-1β Decreases Aneurysm Formation and Progression in a Novel Model of Thoracic Aortic Aneurysms

Abstract

Background Thoracic aortic aneurysms (TAAs) are common, but experimental TAA models are limited and the role of interleukin-1β (IL-1β) is undetermined. Methods and Results IL-1β protein was measured in human TAAs and control aortas, and IL-1β protein was increased ≈20-fold in human TAAs. To develop an experimental model of TAAs, 8- to 10-week-old male C57Bl/6 mice (wild type [WT]) underwent thoracotomy with application of periadventitial elastase (WT TAA) or saline (WT control; n=30 per group). Elastase treatment to thoracic aortas resulted in progressive dilation until day 14 with maximal dilation of 99.6±24.7% compared with 14.4±8.2% for WT saline control (P<0.0001). WT TAAs demonstrated elastin fragmentation, smooth muscle cell loss, macrophage infiltration, and increased IL-1β expression. Next, TAAs were induced in mice deficient of IL-1β (IL-1β knockout) or IL-1 receptor (IL-1R knockout; n=10 each). Genetic deletion of IL-1β and IL-1R significantly decreased thoracic aortic dilation (IL-1β knockout=54.2±16.8% and IL-1R knockout=62.6±17.2% versus WT TAA=104.7±23.8%; P<0.001for both). IL-1β knockout and IL-1R knockout aortas demonstrated preserved elastin and smooth muscle cells with fewer inflammatory cells. Correspondingly, IL-1β and IL-1R knockout aortas had decreased inflammatory cytokine and matrix metalloproteinase 9 expression. Separately, WT mice pretreated with either IL-1R antagonist anakinra (100 mg/kg per day) or vehicle alone (control) underwent elastase treatment. Pretreatment of WT mice with anakinra attenuated TAA formation (control: 99.2±15.5% versus anakinra: 68.3±19.2%; P<0.005). Finally, to investigate treatment of small TAAs, WT mice were treated with anakinra 3 days after TAA induction. Anakinra treatment in WT mice with small TAAs reduced aortic dilation on day 14 (control treatment: 89.1±18.6% versus anakinra treatment: 59.7±25.7%; P=0.01). Conclusions Periadventitial application of elastase to murine thoracic aortas reproducibly produced aneurysms with molecular and histological features consistent with TAA disease. Genetic and pharmacological inhibition of IL-1β decreased TAA formation and progression, indicating that IL-1β may be a potential target for TAA treatment.

Activation of endocannabinoid system is associated with persistent inflammation in human aortic aneurysm

“…So far, all of these facts indicate a very finely tuned inflammatory process in human aortic aneurysms and therefore the recently postulated prognostic value for phosphorylation of c-kit and downstream targets in aneurysm formation fits well in this concept [20]. In this context, recent studies reported that the inhibition of cytokine IL-1 attenuates experimental development of aortic aneurysm [21], as well as activation of TGF-signalling [22]. Future studies should address the exact characterization and cellular imaging of the inflammatory cells, that is, T-cells, macrophage subpopulations, and so forth, in order to better understand their specific contribution during development of human aneurysms.…”

Interleukin-6 Receptor Inhibition Prevents Descending Thoracic Aortic Aneurysm Formation

“…The thoracic and abdominal aorta contain cells of distinct embryologic origins [3]. Additionally, the thoracic aorta has greater elastin content and contains more prominent vaso vasora than the abdominal aorta [4][5][6]. Current nonsurgical therapy for AAA and TAA is aimed at preventing further dilation and includes risk factor reduction and b-adrenergic blockade (for TAA), both with limited efficacy [1,7].…”

Anakinra and etanercept prevent embryo loss in pregnant nonobese diabetic mice

“…In the anakinra and etanercept experiments, the pregnant mice received i.p. injections of 100 mg/dam control IgG, 300 mg/dam anakinra, 100 mg/dam etanercept, or a combination of anakinra and etanercept at the mentioned doses (McCall et al 2012, Johnston et al 2014.…”