Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation

Cardiovascular Research, vol. 120, pp. 581–595

Abstract

AIMS: The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis. METHODS AND RESULTS: Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E-deficient (Apoe-/-) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade. CONCLUSION: Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.

Authors 17

1. Megan Mulholland

   Lund University

   Affiliation as printed

   Department of Clinical Sciences, Cardiovascular Research—Immune Regulation, Lund University , Malmö , Sweden

2. Marie A.C. Depuydt Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University , Leiden , The Netherlands

3. Gabriel Jakobsson

   Lund University

   Affiliation as printed

   Department of Translational Medicine, Cardiac Inflammation, Lund University , Malmö , Sweden

4. Irena Ljungcrantz

   Lund University

   Affiliation as printed

   Department of Clinical Sciences, Cardiovascular Research—Immune Regulation, Lund University , Malmö , Sweden

5. Andrietta Grentzmann

   Lund University

   Affiliation as printed

   Department of Clinical Sciences, Cardiovascular Research—Immune Regulation, Lund University , Malmö , Sweden

6. Fong To

   Lund University

   Affiliation as printed

   Department of Clinical Sciences, Cardiovascular Research—Matrix and Inflammation in Atherosclerosis, Lund University , Malmö , Sweden

7. Eva Bengtsson

   Malmö University · Lund University

   Affiliation as printed

   Biofilms—Research Center for Biointerfaces, Malmö University , Malmö , Sweden

   Department of Biomedical Science, Malmö University , Malmö , Sweden

   Department of Clinical Sciences, Cardiovascular Research—Matrix and Inflammation in Atherosclerosis, Lund University , Malmö , Sweden

8. Elin Jaensson Gyllenbäck
   Affiliation as printed

   Cantargia AB , Lund , Sweden

9. Caitríona Grönberg
   Affiliation as printed

   Cantargia AB , Lund , Sweden

10. Sara Rattik

    Lund University

    Affiliation as printed

    Cantargia AB , Lund , Sweden

    Department of Clinical Sciences, Cardiovascular Research—Immune Regulation, Lund University , Malmö , Sweden

11. David Liberg
    Affiliation as printed

    Cantargia AB , Lund , Sweden

12. Alexandru Șchiopu

    Lund University

    Affiliation as printed

    Department of Translational Medicine, Cardiac Inflammation, Lund University , Malmö , Sweden

13. Harry Björkbacka

    Lund University

    Affiliation as printed

    Department of Clinical Sciences, Cardiovascular Research—Cellular Metabolism and Inflammation, Lund University , Malmö , Sweden

14. Johan Kuiper Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University , Leiden , The Netherlands

15. Ilze Bot Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University , Leiden , The Netherlands

16. Bram Slütter Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University , Leiden , The Netherlands

17. Daniel Engelbertsen corresponding

    Lund University

    Affiliation as printed

    Department of Clinical Sciences, Cardiovascular Research—Immune Regulation, Lund University , Malmö , Sweden