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Nat Med. 2018 Sep;24(9):1418-1429. doi: 10.1038/s41591-018-0124-5. Epub 2018 Jul 23.

Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice.

Author information

1
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
2
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
3
Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
4
Division of Cardiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
5
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
6
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
7
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
8
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
9
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
10
Novartis Institutes for Biomedical Research, Basel, Switzerland.
11
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA. gko@virginia.edu.
12
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA. gko@virginia.edu.

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.

PMID:
30038218
PMCID:
PMC6130822
[Available on 2019-01-23]
DOI:
10.1038/s41591-018-0124-5

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