Abstract 5557: Lack of Interleukin-1 Receptor Antagonist in Inflammatory Cells Causes Spontaneous Femoral Artery Aneurysms in Mice

Abstract

Background: Arterial aneurysms represent a complex degenerative disorder involving chronic arterial wall inflammation and destructive remodeling of structural connective tissue. The relative balance of pro- and anti-inflammatory cytokines likely controls inflammation in the aneurysm wall. The interleukin (IL)-1 receptor antagonist (IL-1Ra) negatively regulates IL-1 signaling. However, the role of IL-1Ra in aneurysm is poorly understood. Methods and Results: IL-1Ra-deficient (IL-1Ra−/−) mice (backcrossed 8 generations to the B6 background) and wild-type (WT) mice did not differ with regard to systolic arterial pressure and plasma lipid levels. However, IL-1Ra−/− mice had spontaneously developed femoral artery aneurysms after 8-month-old, and both maximal vessel area and the intimal + medial area of femoral arteries in IL-1Ra−/− mice were significantly larger compared with WT mice at 9 months of age. Real-time PCR of 9-month-old IL-1Ra−/− mice revealed significantly increased mRNA levels of IL-1 β (6.6-fold, P<0.05), tumor necrosis factor (TNF)- α (12.4-fold, P<0.05) and matrix metaroproteinase-9 (6.0-fold, P<0.01) compared with WT mice. Histological analysis revealed numerous inflammatory cells around the femoral artery aneurysm in IL-1Ra−/− mice, and elastin staining showed destruction of the internal and external elastic lamina in IL-1Ra−/− mice. Immunostaining revealed many macrophages and some CD4-positive T cells in the adventitia. Then we studied the function of macrophage and T cell. After LPS (1 μ g/ml) stimulation, IL-1Ra deficient macrophages produced much higher levels of TNF- α than those from WT mice. Furthermore TNF- α production of T cells from IL-1Ra−/− mice stimulated with anti-CD3 antibody was also higher than those from WT mice. Finally, we performed bone marrow (BM) cell transplantation. We detected femoral artery aneurysms with many inflammatory cells in the adventitia in several WT mice receiving BM cells from IL-1Ra−/− (44%) but not WT mice (0%). Conclusions: This study demonstrates that IL-1Ra-deficiency in inflammatory cells disrupts immune system homeostasis, resulting in the development of autoimmunity and inflammation. Then the inflammation causes spontaneous femoral artery aneurysms in B6 mice.