Lack of Interleukin-1 Receptor Antagonist Modulates Plaque Composition in Apolipoprotein E–Deficient Mice

Abstract

Objective-Interleukin (IL)-1 plays an important role in atherosclerosis. IL-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor of IL-1. However, the role of IL-1Ra in the development of atherosclerosis is poorly understood. Methods and Results-Mice that lacked IL-1Ra (IL-1RaϪ/Ϫ) were crossed with apolipoprotein E-deficient (EϪ/Ϫ) mice and formation of atherosclerotic lesions was analyzed after 16 weeks or 32 weeks consumption of a normal chow diet. This study focused on the comparison of atherosclerotic lesion between IL-1Raϩ/ϩ/apoEϪ/Ϫ (nϭ12) and IL-1Ra/apoEϪ/Ϫ mice (nϭ12), because of the significantly leaner phenotype in IL-1RaϪ/Ϫ/apoEϪ/Ϫ mice compared with the others. Interestingly, atherosclerotic lesion size in IL-1Raϩ/Ϫ/apoEϪ/Ϫ mice at age 16 weeks was significantly increased (30%) compared with IL-1Raϩ/ϩ/apoEϪ/Ϫ mice (PϽ0.05). At 32 weeks, the differences of lesion size between these mice failed to achieve statistical significance. However, immunostaining demonstrated an 86% (PϽ0.0001) increase in the MOMA-2-stained lesion area of IL-1Raϩ/Ϫ/apoEϪ/Ϫ mice. In addition, ␣-actin staining in these lesions was significantly decreased (Ϫ15%) compared with those in IL-1Raϩ/ϩ/apoEϪ/Ϫ mice (PϽ0.05). Conclusions-These

Interleukin-1β Inhibition Prevents Choroidal Neovascularization and Does Not Exacerbate Photoreceptor Degeneration

“…14,16 Neutrophils and macrophages promote CNV 23,26 -28 ; IL-1Ra has been shown to inhibit macrophage recruitment to the atherosclerotic plaque in a mouse model. 2 We therefore tested the influence of IL-1Ra treatment on neutrophil and macrophage recruitment to the laser-injury site as a possible mechanism of CNV inhibition (Figure 2). Interestingly, IL-1Ra treatment significantly increased the number of Ly6G-positive neutrophils at 10 hours, suggesting a possible IL-1␤-dependent negative feedback in neutrophil recruitment.…”

“…2 It might thereby indirectly influence angiogenesis. To test this hypothesis, we visualized neutrophils and macrophages/microglial cells 10 hours (Figure 2 Figure 2G) and macrophage/microglial cell ( Figure 2J) prevalence were quantified.…”

The Effect of Interleukin-1 Receptor Antagonist on Arteries and Cholesterol Metabolism

“…2B) (38). Our real-time polymerase chain reaction (RT-PCR) analysis revealed that deletion of IL-1Ra increases the mRNA expression of the adhesion molecules vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in the aorta, and enhances mRNA levels of monocyte chemoattractant protein (MCP)-1 (38). These changes may contribute to the enhanced accumulation of Mφs in advanced plaques.…”

“…These findings suggest that endogenous IL-1Ra may suppress atherosclerosis. To directly answer the question of whether a deficiency of IL-1Ra promotes the development of ath- (38). Following 32 weeks, the differences in lesion size between these mice failed to achieve statistical significance (38).…”

“…To directly answer the question of whether a deficiency of IL-1Ra promotes the development of ath- (38). Following 32 weeks, the differences in lesion size between these mice failed to achieve statistical significance (38). However, immunostaining demonstrated an 86% increase in the MOMA-2-stained area in IL1Ra +/-/ apoE -/-mice ( Fig.…”