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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 15, 2021
- Source ID
- 10.7554/elife.67932
Entities
People
- Ada Weinstock
- Brian E. Sansbury
- Chiara Giannarelli
- Cyrus A Nikain
- Dawn Fernandez
- Edward A Fisher
- Emily J. Brown
- Gregory Marecki
- Hitoo Nishi
- Jianhua Liu
- Karishma Rahman
- Kelly V. Ruggles
- Matthew Spite
- Michela L Garabedian
- Naveed Akbar
- Or Yaacov
- P'ng Loke
- Prashanthi Menon
- Robin P Choudhury
- Sean P Heffron
- Stephanie Pena
- Stephen A Ramsey
Organizations
- American Heart Association
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Grossman School of Medicine
- Harvard Medical School
- Icahn School of Medicine at Mount Sinai
- National Heart, Lung, and Blood Institute
- National Institutes of Health
- New York University
- Oregon State University
- United States Department of Defense
- University of Oxford