Eur J Pharmacol. 2026 Oct 24:179482. doi: 10.1016/j.ejphar.2026.179482. Online ahead of print.
ABSTRACT
INTRODUCTION: Macrophages are central to atherosclerosis by driving vascular inflammation, plaque growth, and instability. Although interleukin-17D (IL-17D) has been linked to endothelial inflammation, its role in macrophage-mediated atherosclerosis remains unclear.
OBJECTIVES: This study investigated the function and mechanism of macrophage IL-17D in atherosclerosis.
METHODS: Using IL-17D knockout, macrophage-specific IL-17D knockdown, and macrophage-specific Spi-B knockdown mouse models on an ApoE-/- background, we assessed aortic lesion burden, necrotic core formation, macrophage accumulation, inflammatory responses, and macrophage polarization. Mechanistic studies were performed using transcriptomic analysis, ChIP-PCR, and luciferase reporter assays.
RESULTS: IL-17D deficiency markedly reduced atherosclerotic plaque formation in the whole aorta and aortic root, decreased necrotic core size, and limited macrophage accumulation and vascular inflammation. Both in vitro and in vivo, IL-17D deficiency promoted M2 macrophage polarization while suppressing pro-inflammatory cytokines and chemokines. Macrophage-specific IL-17D knockdown similarly attenuated atherosclerotic lesion development and inflammation. Mechanistically, IL-17D deficiency activated the Spi-B-STAT6 transcriptional axis. Macrophage-specific Spi-B knockdown reversed the anti-atherosclerotic effects of IL-17D deficiency, confirming its functional importance. Rosuvastatin suppressed IL-17D expression, and IL-17D repression contributed to its anti-inflammatory and anti-atherogenic effects.
CONCLUSIONS: These findings identify macrophage-derived IL-17D as a key regulator of atherosclerosis. Targeting IL-17D may promote protective M2 polarization and alleviate vascular inflammation, offering a potential therapeutic strategy for atherosclerotic disease.
PMID:42926082 | DOI:10.1016/j.ejphar.2026.179482