Genetic and pharmacologic disruption of interleukin-1β signaling inhibits experimental aortic aneurysm formation.

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- to 12-week-old male C57Bl/6 mice after elastase aortic perfusion (wild-type [WT]) compared with saline perfusion. Mice with genetic deletion of IL-1β (IL-1β knockout [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 with 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 with 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 after AAA initiation with elastase demonstrated significant protection against AAA progression and had decreased aortic dilation compared with 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.