Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis
- New York University Grossman School of Medicine, United States
- University of Oxford, United Kingdom
- Harvard Medical School, United States
- Icahn School of Medicine at Mount Sinai, United States
- NYU Langone Health, United States
- Oregon Health Sciences University, United States
- 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.
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Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosisNCBI Gene Expression Omnibus, GSE168542.
Article and author information
Author details
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.
Reviewing Editor
- Jameel Iqbal, James J. Peters Veterans Affairs Medical Center, United States
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.
Version history
- Received: February 27, 2021
- Accepted: March 1, 2021
- Accepted Manuscript published: March 15, 2021 (version 1)
- Accepted Manuscript updated: March 17, 2021 (version 2)
- 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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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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