Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis
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.
-
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.
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
- Jameel Iqbal, James J. Peters Veterans Affairs Medical Center, United States
Publication 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.
Metrics
-
- 2,906
- Page views
-
- 399
- Downloads
-
- 15
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
Newborns are unable to reach the adult-level humoral immune response partly due to the potent immunoregulatory role of IL-10. Increased IL-10 production by neonatal B cells has been attributed to the larger population of IL-10-producting CD43+ B-1 cells in neonates. Here, we show that neonatal mouse CD43- non-B-1 cells also produce substantial amounts of IL-10 following B cell antigen receptor (BCR) activation. In neonatal mouse CD43- non-B-1 cells, BCR engagement activated STAT5 under the control of phosphorylated forms of signaling molecules Syk, Btk, PKC, FAK and Rac1. Neonatal STAT5 activation led to IL-6 production, which in turn was responsible for IL-10 production in an autocrine/paracrine fashion through the activation of STAT3. In addition to the increased IL-6 production in response to BCR stimulation, elevated expression of IL-6Rα expression in neonatal B cells rendered them highly susceptible to IL-6 mediated STAT3 phosphorylation and IL-10 production. Finally, IL-10 secreted from neonatal mouse CD43- non-B-1 cells was sufficient to inhibit TNF-α secretion by macrophages. Our results unveil a distinct mechanism of IL-6-dependent IL-10 production in BCR-stimulated neonatal CD19+CD43- B cells.
-
- Chromosomes and Gene Expression
- Immunology and Inflammation
Maternal pre-pregnancy (pregravid) obesity is associated with adverse outcomes for both mother and offspring. Amongst the complications for the offspring is increased susceptibility and severity of neonatal infections necessitating admission to the intensive care unit, notably bacterial sepsis and enterocolitis. Previous studies have reported aberrant responses to LPS and polyclonal stimulation by umbilical cord blood monocytes that were mediated by alterations in the epigenome. In this study, we show that pregravid obesity dysregulates umbilical cord blood monocyte responses to bacterial and viral pathogens. Specifically, interferon-stimulated gene expression and inflammatory responses to respiratory syncytial virus (RSV) and E. coli were significantly dampened, respectively . Although upstream signaling events were comparable, translocation of the key transcription factor NF-κB and chromatin accessibility at pro-inflammatory gene promoters following TLR stimulation was significantly attenuated. Using a rhesus macaque model of western style diet-induced obesity, we further demonstrate that this defect is detected in fetal peripheral monocytes and tissue-resident macrophages during gestation. Collectively, these data indicate that maternal obesity alters metabolic, signaling, and epigenetic profiles of fetal monocytes leading to a state of immune paralysis during late gestation and at birth.