IL-17D has been found to induce inflammatory cytokines in endothelial cells, but its exact role in atherosclerosis (AS) is unclear. This study aims to explore IL-17D' function in AS development. The expression of IL-17D was examined in AS patients and mice, and its clinical significance was evaluated in patients with acute coronary syndrome (ACS). Apolipoprotein E and IL-17D deficient mice (ApoEIL-17D) were generated for this study. The inflammation response and ferroptosis status in vascular endothelial cells were assessed following IL-17D treatment. Flow cytometry was used to identify the functional receptor of IL-17D. Additionally, RNA-seq was utilized to analyze the miRNA expression profiles induced by IL-17D. Plasma levels of IL-17D were elevated in both AS patients and mice, and were correlated with an increased incidence of major adverse cardiovascular events (MACEs). ApoEIL-17D mice displayed reduced inflammation and fewer atherosclerotic lesions. Treatment with IL-17D resulted in elevated levels of IL-6, IL-8, and ROS, as well as impaired cell viability and GSH production in endothelial cells. Ferroptosis inhibitor (Fer-1) suppressed the proinflammatory effects by IL-17D. Furthermore, CD93 was identified as the functional receptor for IL-17D in endothelial cells. The inhibition of miR-181a-5p led to a significant increase in cell viability and GSH levels, alongside a reduction in ROS and IL-6/IL-8 levels, while the suppression of SLC7A11 abolished these effects. Our findings suggest that IL-17D promotes endothelial inflammation by causing ferroptosis via CD93/miR-181a-5p/SLC7A11 signaling pathway. These insights advance our understanding of the pathophysiology of AS and identify a potential target for therapeutic intervention.
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| http://dx.doi.org/10.1016/j.intimp.2024.113558 | DOI Listing |
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