Genetic and Pharmacologic Disruption of Interleukin-1β Signaling Inhibits Experimental Aortic Aneurysm Formation

Abstract

Objective Abdominal aortic aneurysms (AAAs) are common, but their exact pathogenesis remains unknown and no specific medical therapies are available. We sought to evaluate interleukin-1β (IL-1β) and interleukin-1 receptor (IL-1R) in an experimental AAA model to identify novel therapeutic targets for AAA treatment. Methods and Results IL-1β mRNA and protein levels were significantly elevated in abdominal aortas of 8-12 week old male C57Bl/6 mice following elastase aortic perfusion (WT) compared to saline perfusion. Mice with genetic deletion of IL-1β (IL-1β KO) or IL-1R (IL-1R KO) that underwent elastase perfusion demonstrated significant protection against AAA formation, with maximal aortic dilations of 38.0±5.5% for IL-1β KO and 52.5±4.6% for IL-1R KO compared to 89.4±4.0% for WT mice (p<0.005). Correspondingly, IL-1β KO and IL-1R KO aortas had reduced macrophage and neutrophil staining with greater elastin preservation compared to WT. In WT mice pretreated with escalating doses of the IL-1R antagonist anakinra, there was a dose-dependent decrease in maximal aortic dilation (R=−0.676, p <0.0005). Increasing anakinra doses correlated with decreasing macrophage staining and elastin fragmentation. Lastly, WT mice treated with anakinra 3 or 7 days following AAA initiation with elastase demonstrated significant protection against AAA progression and had decreased aortic dilation compared to control mice. Conclusions IL-1β is critical for AAA initiation and progression, and IL-1β neutralization through genetic deletion or receptor antagonism attenuates experimental AAA formation. Disrupting IL-1β signaling offers a novel pathway for AAA treatment.

A Dipeptidyl Peptidase-4 Inhibitor but not Incretins Suppresses Abdominal Aortic Aneurysms in Angiotensin II-Infused Apolipoprotein E-Null Mice

“…It has been reported that the IL-1 gene and protein expression levels were substantially elevated in human AAAs 27,28) , and circulating IL-1 levels were elevated in patients with AAA 29) . Moreover, genetic depletion of IL-1 and the IL-1 receptor as well as pharmacological inhibition of the IL-1 receptor suppressed AAA formation in mice 30) . Ta et al reported that a DPP-4I suppressed IL-1 expression in cultured human monocytes 31) .…”

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

“…Moreover, IL1β-or IL1R-gene deficiency protected against elastase perfusion-induced AAA formation, which is associated with a reduction in macrophage and neutrophil infiltration, as well as elastin preservation [85]. In the same study, pretreatment with Anakinra, an IL1R antagonist, significantly inhibited AAA enlargement, macrophage infiltration and elastin disruption [85].…”

“…Interleukin-1 (IL-1) is a key cytokine in the inflammatory cascade [84] and is a central factor and powerful modulator of AAA genesis and progression [85][86][87]. Production of IL1β was significantly higher in aneurysmal tissues than control aortic tissue from cadaveric donors [87].…”

“…Johnston et al demonstrated that IL-1β expression was elevated in the abdominal aorta of B6 mice after elastase aortic perfusion [85]. Moreover, IL1β-or IL1R-gene deficiency protected against elastase perfusion-induced AAA formation, which is associated with a reduction in macrophage and neutrophil infiltration, as well as elastin preservation [85].…”

A pregnancy‐associated nonfamilial case of PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, acne) syndrome

“…Inflammatory cytokines, such as TNF‐ α and IL‐1 β , are known to induce the proliferation of smooth muscle cells in vascular tissue 8. In addition, administration of anakinra, an inhibitor of IL‐1 β , or deletion of the IL‐1 β coding gene has been shown to increase the diameter of aortic aneurysms in animal models 9.…”