Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis

  1. Ada Weinstock
  2. Karishma Rahman
  3. Or Yaacov
  4. Hitoo Nishi
  5. Prashanthi Menon
  6. Cyrus A Nikain
  7. Michela L Garabedian
  8. Stephanie Pena
  9. Naveed Akbar
  10. Brian E Sansbury
  11. Sean P Heffron
  12. Jianhua Liu
  13. Gregory Marecki
  14. Dawn Fernandez
  15. Emily J Brown
  16. Kelly V Ruggles
  17. Stephen Ramsey
  18. Chiara Giannarelli
  19. Matthew Spite
  20. Robin Choudhury
  21. P'ng Loke
  22. Edward A Fisher  Is a corresponding author
  1. New York University Grossman School of Medicine, United States
  2. University of Oxford, United Kingdom
  3. Harvard Medical School, United States
  4. Icahn School of Medicine at Mount Sinai, United States
  5. NYU Langone Health, United States
  6. Oregon Health Sciences University, United States
  7. Brigham's and Women's Hospital, Harvard Medical School, United States

Abstract

Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low, and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.

Data availability

The RNA sequencing data will be deposited in GEO under accession number GSE168542.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ada Weinstock

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3619-3388
  2. Karishma Rahman

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Or Yaacov

    Medicine/Cardiology, New York University Grossman School of Medicine, New york, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8496-2607
  4. Hitoo Nishi

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Prashanthi Menon

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Cyrus A Nikain

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Michela L Garabedian

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Stephanie Pena

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Naveed Akbar

    Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Brian E Sansbury

    Center for Experimental Therapeutics and Reperfusion, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Sean P Heffron

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jianhua Liu

    Surgery, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Gregory Marecki

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Dawn Fernandez

    Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Emily J Brown

    Medicine/Cardiology, New York University Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Kelly V Ruggles

    Department of Medicine, NYU Langone Health, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0152-0863
  17. Stephen Ramsey

    Oregon Health Sciences University, Corvallis, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Chiara Giannarelli

    Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Matthew Spite

    Center for Experimental Therapeutics and Reperfusion Injury, Brigham's and Women's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Robin Choudhury

    Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  21. P'ng Loke

    Department of Microbiology and Immunology, NYU Langone Health, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6211-3292
  22. Edward A Fisher

    Division of Cardiology, Center for the Prevention of Cardiovascular Disease, Cardiovascular Research Center, New York University Grossman School of Medicine, New York, United States
    For correspondence
    Edward.Fisher@nyulangone.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9802-143X

Funding

National Heart, Lung, and Blood Institute (K23HL135398)

  • Sean P Heffron

National Heart, Lung, and Blood Institute (K99HL151963)

  • Ada Weinstock

American Heart Association (20SFRN35210252)

  • Chiara Giannarelli

National Heart, Lung, and Blood Institute (R03HL13528)

  • Chiara Giannarelli

National Heart, Lung, and Blood Institute (K23HL111339)

  • Chiara Giannarelli

National Heart, Lung, and Blood Institute (R21TR001739)

  • Chiara Giannarelli

National Heart, Lung, and Blood Institute (UH2/3TR002067)

  • Chiara Giannarelli

National Heart, Lung, and Blood Institute (5T23HL007824)

  • Dawn Fernandez

National Heart, Lung, and Blood Institute (HL106173)

  • Matthew Spite

National Heart, Lung, and Blood Institute (GM095467)

  • Matthew Spite

National Heart, Lung, and Blood Institute (HL084312)

  • Edward A Fisher

National Heart, Lung, and Blood Institute (HL136044)

  • Brian E Sansbury

Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (AI130945)

  • P'ng Loke

Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (AI133977)

  • P'ng Loke

National Heart, Lung, and Blood Institute (HL084312)

  • P'ng Loke

U.S. Department of Defense (W81XWH-16-1-0256)

  • P'ng Loke

American Heart Association (18POST34080390)

  • Ada Weinstock

Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (T32AI100853)

  • Karishma Rahman

National Heart, Lung, and Blood Institute (F30HL131183)

  • Karishma Rahman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to the protocol (number IA16-00494) approved by the Institutional Animal Care and Use Committee of the New York University School of Medicine.

Reviewing Editor

  1. Jameel Iqbal, James J. Peters Veterans Affairs Medical Center, United States

Publication history

  1. Received: February 27, 2021
  2. Accepted: March 1, 2021
  3. Accepted Manuscript published: March 15, 2021 (version 1)
  4. Accepted Manuscript updated: March 17, 2021 (version 2)
  5. Version of Record published: March 25, 2021 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Ada Weinstock
  2. Karishma Rahman
  3. Or Yaacov
  4. Hitoo Nishi
  5. Prashanthi Menon
  6. Cyrus A Nikain
  7. Michela L Garabedian
  8. Stephanie Pena
  9. Naveed Akbar
  10. Brian E Sansbury
  11. Sean P Heffron
  12. Jianhua Liu
  13. Gregory Marecki
  14. Dawn Fernandez
  15. Emily J Brown
  16. Kelly V Ruggles
  17. Stephen Ramsey
  18. Chiara Giannarelli
  19. Matthew Spite
  20. Robin Choudhury
  21. P'ng Loke
  22. Edward A Fisher
(2021)
Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis
eLife 10:e67932.
https://doi.org/10.7554/eLife.67932
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