Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33720008.
- Also identified by DOI 10.7554/eLife.67932 and PMC identifier 7994001.
- Licence recorded as CC0.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>Il4<sup>-/-</sup>Il13<sup>-/-</sup></i> 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 PGE<sub>2</sub>/STAT3 axis.
Medical subject headings
- Atherosclerosis
- Interleukin-4
- Macrophages
- Wnt Signaling Pathway