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.
-
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
-
- 3,111
- Page views
-
- 415
- Downloads
-
- 18
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
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)
Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis
eLife 10:e67932.
https://doi.org/10.7554/eLife.67932
Further reading
-
- Computational and Systems Biology
- Immunology and Inflammation
To appropriately defend against a wide array of pathogens, humans somatically generate highly diverse repertoires of B cell and T cell receptors (BCRs and TCRs) through a random process called V(D)J recombination. Receptor diversity is achieved during this process through both the combinatorial assembly of V(D)J-genes and the junctional deletion and insertion of nucleotides. While the Artemis protein is often regarded as the main nuclease involved in V(D)J recombination, the exact mechanism of nucleotide trimming is not understood. Using a previously published TCRβ repertoire sequencing data set, we have designed a flexible probabilistic model of nucleotide trimming that allows us to explore various mechanistically interpretable sequence-level features. We show that local sequence context, length, and GC nucleotide content in both directions of the wider sequence, together, can most accurately predict the trimming probabilities of a given V-gene sequence. Because GC nucleotide content is predictive of sequence-breathing, this model provides quantitative statistical evidence regarding the extent to which double-stranded DNA may need to be able to breathe for trimming to occur. We also see evidence of a sequence motif that appears to get preferentially trimmed, independent of GC-content-related effects. Further, we find that the inferred coefficients from this model provide accurate prediction for V- and J-gene sequences from other adaptive immune receptor loci. These results refine our understanding of how the Artemis nuclease may function to trim nucleotides during V(D)J recombination and provide another step toward understanding how V(D)J recombination generates diverse receptors and supports a powerful, unique immune response in healthy humans.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Streptococcus pneumoniae is a major pathogen in children, elderly subjects and immunodeficient patients. PTX3 is a fluid phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal infection. In a murine model of invasive pneumococcal infection, PTX3 was strongly induced in non-hematopoietic (particularly, endothelial) cells. The IL-1β/MyD88 axis played a major role in regulation of the Ptx3 gene expression. Ptx3-/- mice presented more severe invasive pneumococcal infection. Although high concentrations of PTX3 had opsonic activity in vitro, no evidence of PTX3-enhanced phagocytosis was obtained in vivo. In contrast, Ptx3-deficient mice showed enhanced recruitment of neutrophils and inflammation. Using P-selectin deficient mice, we found that protection against pneumococcus was dependent upon PTX3-mediated regulation of neutrophil inflammation. In humans, PTX3 genetic polymorphisms were associated with invasive pneumococcal infections. Thus, this fluid phase PRM plays an important role in tuning inflammation and resistance against invasive pneumococcal infection.
