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Updated: Feb 7, 2026
Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice
Delphine Gomez1,2,3,4, Richard A Baylis1,5, Brittany G Durgin1,2
1Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
Abstract:
Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, in which post-myocardial infarction subjects were treated with an IL-1β antibody. Here, we performed intervention studies in which smooth muscle cell (SMC) lineage-tracing Apoe-/- mice with advanced atherosclerosis were treated with anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage numbers in the fibrous cap. Moreover, although IL-1β antibody treatment had no effect on lesion size, it completely inhibited beneficial outward remodeling. We also found that SMC-specific knockout of Il1r1 (encoding IL-1 receptor type 1) resulted in smaller lesions nearly devoid of SMCs and lacking a fibrous cap, whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, these results show that IL-1β has multiple beneficial effects in late-stage murine atherosclerosis, including promotion of outward remodeling and formation and maintenance of an SMC- and collagen-rich fibrous cap.
Insights
Targeting interleukin-1 beta (IL-1β) surprisingly worsened advanced atherosclerosis in mice. Blocking IL-1β reduced smooth muscle cells and collagen, impairing plaque stability and outward remodeling, contrary to expectations.
Area of Science:
- Cardiovascular Research
- Immunology
- Atherosclerosis Pathophysiology
Background:
- Understanding late-stage atherosclerotic plaque stability is crucial but limited.
- Reducing inflammation is hypothesized to improve plaque stability, as explored in the CANTOS trial using IL-1β blockade.
Purpose of the Study:
- To investigate the role of IL-1β in advanced atherosclerotic plaque stability and remodeling in a murine model.
- To determine the specific cellular targets of IL-1β's effects on plaque composition and stability.
Main Methods:
- Intervention studies using anti-IL-1β or control antibodies in smooth muscle cell (SMC) lineage-tracing Apoe-/- mice on a Western diet.
- SMC-specific and macrophage-selective knockout of IL-1 receptor type 1 (Il1r1) were performed.
- Analysis of plaque composition (SMC content, collagen, macrophages) and outward remodeling.
Main Results:
- Anti-IL-1β treatment reduced SMC and collagen content while increasing macrophages in the fibrous cap.
- IL-1β blockade inhibited beneficial outward remodeling without affecting lesion size.
- SMC-specific Il1r1 knockout led to smaller lesions lacking SMCs and fibrous caps.
- Macrophage-selective Il1r1 loss did not impact lesion size or composition.
Conclusions:
- IL-1β plays a beneficial role in late-stage murine atherosclerosis.
- IL-1β promotes outward remodeling and the formation/maintenance of an SMC- and collagen-rich fibrous cap.
- Targeting IL-1β may negatively impact atherosclerotic plaque stability.
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