1. Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis
- Author
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Chiara Giannarelli, Stephanie Pena, Robin P. Choudhury, Matthew Spite, Naveed Akbar, Stephen A. Ramsey, Karishma Rahman, Or Yaacov, Emily J. Brown, Kelly V. Ruggles, Dawn M. Fernandez, Gregory Marecki, Edward A. Fisher, Michela L. Garabedian, P'ng Loke, Sean P. Heffron, Prashanthi Menon, Cyrus A Nikain, Brian E. Sansbury, Jianhua Liu, Hitoo Nishi, and Ada Weinstock
- Subjects
Male ,0301 basic medicine ,Mouse ,Disease ,030204 cardiovascular system & hematology ,medicine.disease_cause ,STAT3 ,Mice ,Immunology and Inflammation ,0302 clinical medicine ,Macrophage ,Biology (General) ,Wnt Signaling Pathway ,STAT6 ,Mutation ,biology ,General Neuroscience ,Wnt signaling pathway ,General Medicine ,pge2 ,Medicine ,Female ,medicine.symptom ,Research Article ,atherosclerosis resolution ,Human ,QH301-705.5 ,Science ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Wnt ,03 medical and health sciences ,medicine ,Animals ,Humans ,Interleukin 4 ,Dose-Response Relationship, Drug ,General Immunology and Microbiology ,business.industry ,Macrophages ,Atherosclerosis ,IL4 ,030104 developmental biology ,Cancer research ,biology.protein ,Interleukin-4 ,business - 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.
- Published
- 2021