Inflammatory Cytokine IL-1β Downregulates Endothelial LRP1 via MicroRNA-mediated Gene Silencing
| Autor: | Carlos J. Rodriguez-Ortiz, Masashi Kitazawa, Heng-Wei Hsu, Joannee Zumkehr |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Aging interleukin-1β medicine.medical_treatment Interleukin-1beta Neurodegenerative Alzheimer's Disease interleukin-1 beta NF-κB neuroinflammation chemistry.chemical_compound 0302 clinical medicine 2.1 Biological and endogenous factors Psychology Aetiology microRNA General Neuroscience NF-kappa B LRP1 endothelial LRP1 Cell biology Cytokine Transcytosis Cytokines Cognitive Sciences Alzheimer’s disease Low Density Lipoprotein Receptor-Related Protein-1 Biotechnology Article 03 medical and health sciences Downregulation and upregulation medicine Genetics Acquired Cognitive Impairment Gene silencing Humans Gene Silencing Neuroinflammation Neurology & Neurosurgery Amyloid beta-Peptides Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Endothelial Cells Brain Disorders MicroRNAs 030104 developmental biology chemistry Dementia 030217 neurology & neurosurgery |
| Zdroj: | Neuroscience |
| Popis: | Effective clearance of neurotoxic amyloid-beta (Aβ) from the brain is a critical process to prevent Alzheimer’s disease (AD). One major clearance mechanism is Aβ 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 Aβ clearance. Recently, we demonstrated that pro-inflammatory cytokines IL-1β, IL-6 and TNF-α, 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-1β 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 ng/ml IL-1β. 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-1β. Synthetic microRNA-205-5p, -200b-3p, and -200c-3p mimics recapitulated LRP1 loss in MVECs without IL-1β, and their synthetic antagomirs effectively reversed IL-1β-mediated LRP1 loss. Importantly, we found that the expression of these three microRNAs was controlled by NF-κB as pharmacological NF-κB inhibitor, BMS-345541, inhibited the IL-1β-mediated upregulation of these microRNAs and rescued LRP1 expression. siRNA-mediated silencing of IκB in MVECs elevated microRNA-200b-3p and decreased LRP1 transcript, partially confirming our overall findings. In conclusion, our study provides a mechanism by which pro-inflammatory IL-1β 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. |
| Databáze: | OpenAIRE |
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