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.

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Acknowledgements

We thank the Owens laboratory members for their input. We thank P. Libby, M. Nahrendorf, and P. Swirski for their constructive discussion during the project completion. We thank E. Greene for her assistance in generating the SMC-specific Il1r1 knockout mice, A. Nguyen for performing retro-orbital injections, and M. McCanna for technical support. We thank the University of Pittsburgh Center for Biologic Imaging for their assistance with confocal microscopy. This work was supported by NIH grants R01 HL121008, R01 HL132904, and R01 HL136314 to G.K.O. D.G. was supported by Scientific Development Grant 15SDG25860021 from the American Heart Association. R.A.B. was supported by NIH grant F30 HL136188. B.G.D. was supported by a Predoctoral Fellowship from the American Heart Association (14PRE20380659). C.S.H. was supported by K22HL117917. The generation of the IL1R1fl/fl mice was funded by FP7/EU Project MUGEN (MUGEN LSHG-CT-2005-005203) to W.M. and by MRC research (G0801296) to E.P.

Author information

Affiliations

  1. Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA

    • Delphine Gomez
    • , Richard A. Baylis
    • , Brittany G. Durgin
    • , Alexandra A. C. Newman
    • , Gabriel F. Alencar
    •  & Gary K. Owens
  2. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA

    • Delphine Gomez
    • , Brittany G. Durgin
    •  & Gary K. Owens
  3. Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA

    • Delphine Gomez
    • , Sidney Mahan
    •  & Cynthia St. Hilaire
  4. Division of Cardiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    • Delphine Gomez
    •  & Cynthia St. Hilaire
  5. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA

    • Richard A. Baylis
    • , Alexandra A. C. Newman
    •  & Gabriel F. Alencar
  6. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    • Werner Müller
    •  & Emmanuel Pinteaux
  7. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany

    • Ari Waisman
  8. Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

    • Sheila E. Francis
  9. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    • Gwendalyn J. Randolph
  10. Novartis Institutes for Biomedical Research, Basel, Switzerland

    • Hermann Gram

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Contributions

D.G. and G.K.O. originally conceived of and designed the experiments. D.G. performed experiments, analyzed data, performed statistical analysis, and wrote the manuscript. R.A.B. designed and performed experiments, analyzed data, and contributed to manuscript writing. B.G.D. performed staining and data analysis. A.A.C.N. performed staining and data analysis of necrotic core and Ter119 data. G.F.A. analyzed the RNA-seq dataset. S.M. performed staining and analyzed data. C.S.H. performed calcification staining. A.W., W.M., S.E.F., and E.P. provided Il1r1fl/fl mice. G.J.R. helped with the monocyte trafficking assay. H.G. provided the IL-1β antibody and the IgG control and helped in experimental design. G.K.O. supervised the project. All co-authors read the manuscript.

Competing interests

H.G. is a full-time employee of Novartis Pharma AG, Basel.

Corresponding author

Correspondence to Gary K. Owens.

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https://doi.org/10.1038/s41591-018-0124-5