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

Nature Medicine volume 24, pages 1418–1429 (2018)Cite this article

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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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Fig. 1: IL-1β antibody treatment results in systemic and local downregulation of IL-1 signaling and pro-inflammatory pathways.
Fig. 2: IL-1β inhibition induces multiple detrimental changes in the pathogenesis of late-stage atherosclerotic lesions, including loss of an SMC-rich fibrous cap and inhibition of beneficial outward remodeling.
Fig. 3: A three-week course of IL-1β antibody treatment results in an increased number of macrophages within the fibrous cap.
Fig. 4: IL-1β inhibition for three-weeks results in increased proliferation of local macrophages but no change in monocyte trafficking or apoptosis.
Fig. 5: IL-1 signaling within SMCs is required for SMC investment into the lesion and the fibrous cap.
Fig. 6: IL-1β inhibition is associated with polarization of fibrous cap macrophages to an M2 phenotype.

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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.

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Authors and 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.

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Correspondence to Gary K. Owens.

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

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Gomez, D., Baylis, R.A., Durgin, B.G. et al. Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice. Nat Med 24, 1418–1429 (2018). https://doi.org/10.1038/s41591-018-0124-5

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