Abstract Background Immune cells play a central role in the development of atherosclerotic lesions, adopting distinct phenotypes depending on their microenvironment. Asthma is characterized by chronic, systemic type 2 inflammation driven by elevated levels of interleukin (IL)-4 and IL-13 with increased risk for developing cardiovascular disease. However, especially IL13 was associated with an amelioration of atherosclerosis. Purpose In this project, we aim to elucidate how alterations in the receptor for IL-4 and IL-13, IL4Rα-mediated signalling affect the development of atherosclerosis to understand potential risks when this signalling axis is inhibited for targeting Type 2 immunity diseases. Methods Wilde-type (WT) and IL-4Rα knockout (IL-4Rα KO) mice on an LDL receptor knockout background were fed a high-fat diet (HFD) with 21 % fat and 0.20 % cholesterol for 4 weeks or 14 weeks. Whole blood, aorta and hearts were collected and analysed. Human monocyte-derived macrophages were treated with oxidized low-density lipoprotein (oxLDL) in the presence or absence of IL-4 and IL-13 and foam cell development was determined. All animal studies complied with 3R guidelines and were approved by the Animal Care and Use Committee of our Medical University and the Austrian Ministry of Sciences. Experiments involving human material were conducted in accordance with the ethical board and included informed consent. Results L4Rα deficiency accelerated atherosclerotic lesion development in the aorta after 4 weeks of HFD, with lesions remaining larger in the thoracic and lumbar regions after 14 weeks. Collagen and lipid content were unchanged, but elastin fibre breaks were increased, suggesting reduced plaque stability. After 14 weeks of HFD, IL4Rα-deficient mice showed more CD4 T cells and a trend toward fewer alternatively activated CD206 macrophages, while CD80 macrophage numbers remained similar to WT. Plasma MCP-1 levels were elevated in IL4Rα-deficient mice at 4 weeks but normalized by 14 weeks, indicating an earlier inflammatory response. Trem2 foam cells - key drivers of plaque progression - were also increased at 14 weeks. In vitro, IL-4/IL-13 signalling reduced foam cell formation in human macrophages by lowering CD36 expression and oxLDL uptake. OxLDL-induced STAT5 phosphorylation and rerouting of pSTAT5 to mitochondria to fuel foam cell differentiation was inhibited by IL-4/IL-13 signaling that rerouted pSTAT5 to the nucleus thereby retaining cellular metabolism. Consistently, fewer pSTAT5-positive cells were found in plaques of IL4Rα-deficient mice. Overall, IL-4/IL-13 signalling appears to redirect pSTAT5 to the nucleus, thereby limiting foam cell formation and slowing atherosclerotic plaque development Conclusion In conclusion our data emphasize an atheroprotective function of IL-4/IL-13 signaling via preventing oxLDL induced foam cell formation.
Kral-Pointner et al. (2026) studied this question.