eLife (Mar 2021)
Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis
- Ada Weinstock,
- Karishma Rahman,
- Or Yaacov,
- Hitoo Nishi,
- Prashanthi Menon,
- Cyrus A Nikain,
- Michela L Garabedian,
- Stephanie Pena,
- Naveed Akbar,
- Brian E Sansbury,
- Sean P Heffron,
- Jianhua Liu,
- Gregory Marecki,
- Dawn Fernandez,
- Emily J Brown,
- Kelly V Ruggles,
- Stephen A Ramsey,
- Chiara Giannarelli,
- Matthew Spite,
- Robin P Choudhury,
- P'ng Loke,
- Edward A Fisher
Affiliations
- Ada Weinstock
- ORCiD
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Karishma Rahman
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Or Yaacov
- ORCiD
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Hitoo Nishi
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Prashanthi Menon
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Cyrus A Nikain
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Michela L Garabedian
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Stephanie Pena
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Naveed Akbar
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
- Brian E Sansbury
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States
- Sean P Heffron
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States; NYU Center for the Prevention of Cardiovascular Disease, New York University Grossman School of Medicine, New York, United States
- Jianhua Liu
- Department of Surgery, Mount Sinai School of Medicine, New York, United States
- Gregory Marecki
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Dawn Fernandez
- Cardiovascular Research Center, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
- Emily J Brown
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States
- Kelly V Ruggles
- ORCiD
- Division of Translational Medicine, Department of Medicine, New York University Langone Health, Institute for Systems Genetics, New York University Grossman School of Medicine, New York, United States
- Stephen A Ramsey
- Department of Biomedical Sciences, School of Electrical Engineering and Computer Science, Oregon State University, Corvallis, United States
- Chiara Giannarelli
- Cardiovascular Research Center, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Microbiology (Parasitology), New York University School of Medicine, New York, United States
- Matthew Spite
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States
- Robin P Choudhury
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
- P'ng Loke
- ORCiD
- Acute Vascular Imaging Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
- Edward A Fisher
- ORCiD
- Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States; NYU Center for the Prevention of Cardiovascular Disease, New York University Grossman School of Medicine, New York, United States; Departments of Cell Biology and Microbiology, New York University Grossman School of Medicine, New York, United States
- DOI
- https://doi.org/10.7554/eLife.67932
- Journal volume & issue
-
Vol. 10
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.
Keywords
