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
Further reading
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- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
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- Immunology and Inflammation
Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
