Inflammatory Cytokine IL-1 beta Downregulates Endothelial LRP1 via MicroRNA-mediated Gene Silencing

摘要

Effective clearance of neurotoxic amyloid-beta (A beta) from the brain is a critical process to prevent Alzheimer's disease (AD). One major clearance mechanism is A beta transcytosis mediated by low-density lipoprotein receptor-related protein 1 (LRP1) in capillary endothelial cells. A marked loss of endothelial LRP1 is found in AD brains and is believed to significantly impair A beta clearance. Recently, we demonstrated that pro-inflammatory cytokines IL-1 beta, IL-6 and TNF-alpha, significantly down-regulated LRP1 in human primary microvascular endothelial cells (MVECs). In this study, we sought to determine the underlying molecular mechanism by which IL-1 beta led to LRP1 loss in MVECs. Reduced LRP1 protein and transcript were detected up to 24 h post-exposure and returned to the baseline levels after 48 h post-exposure with 1 ngiml IL-1 beta. This reduction was in part mediated by microRNA-205-5p, -200b-3p, and -200c-3p, as these microRNAs were concomitantly upregulated in MVECs exposed to IL-113. Synthetic microRNA-205-5p, -200b-3p, and -200c-3p mimics recapitulated LRP1 loss in MVECs without IL-1 beta, and their synthetic antagomirs effectively reversed IL-1 beta-mediated LRP1 loss. Importantly, we found that the expression of these three microRNAs was controlled by NF-kappa B as pharmacological NF-kappa B inhibitor, BMS-345541, inhibited the IL-1 beta-mediated upregulation of these microRNAs and rescued LRP1 expression. siRNA-mediated silencing of I kappa B in MVECs elevated microRNA-200b-3p and decreased LRP1 transcript, partially confirming our overall findings. In conclusion, our study provides a mechanism by which proinflammatory IL-1 beta instigates the suppression of LRP1 expression in MVECs. Our findings could implicate spatiotemporal loss of LRP1 and impairment of the LRP1-mediated clearance mechanism by endothelial cells. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.