Interleukin-36γ aggravates macrophage foam cell formation and atherosclerosis progression in ApoE knockout mice

•IL-36γ exacerbates atherosclerosis development in ApoE−/− mice.•RNA sequencing reveals that IL-36γ regulates the transcriptome of macrophages.•IL-36γ enhances foam cell formation and increases macrophage cholesterol accumulation.•IL-36γ modulates CD36 expression through PI3K pathway. Atherosclerosis-related cardiovascular diseases are the leading cause of mortality worldwide. Macrophage-derived foam cell formation is a critical early event in atherogenesis. However, the molecular pathways involved in this disease have not been fully elucidated. Interleukin (IL)-36 plays a crucial role in inflammation, and this study was conducted to investigate the possible role of IL-36γ in the pathogenesis and regulation of atherosclerosis. In this study, we show that IL-36γ regulates inflammatory responses and lipoprotein metabolic processes in macrophages and exerts its atherosclerosis-promoting effects by increasing macrophage foam cell formation and uptake of oxidized low-density lipoproteins. Mechanistically, IL-36γ specifically upregulates expression of the scavenger receptor CD36 through the phosphoinositide 3-kinase pathway in macrophages. These results contribute to our understanding of IL-36γ as a novel regulator of foam cell formation and atherogenesis progression.