Ethanol mimics ligand-mediated activation and endocytosis of IL-1RITLR4 receptors vialipid raftscaveolae in astroglial cells
| Autor: | Ana M. Blanco, Sara Fernandez-Lizarbe, Consuelo Guerri, Amparo Pérez-Aragó |
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| Rok vydání: | 2008 |
| Předmět: |
Lipopolysaccharides
Time Factors Interleukin-1beta Interleukin-1 receptor Biology Caveolae Endocytosis Biochemistry Cellular and Molecular Neuroscience medicine Animals Receptor Lipid raft Cells Cultured Cerebral Cortex Analysis of Variance Microscopy Confocal Dose-Response Relationship Drug Ethanol Endoplasmic reticulum Central Nervous System Depressants Rats Cell biology Toll-Like Receptor 4 Protein Transport medicine.anatomical_structure Animals Newborn Astrocytes Neuroglia lipids (amino acids peptides and proteins) Signal Transduction Astrocyte |
| Zdroj: | Journal of Neurochemistry. 106:625-639 |
| ISSN: | 1471-4159 0022-3042 |
| Popis: | We have recently reported that ethanol-induced inflammatory processes in the brain and glial cells are mediated via the activation of interleukin-1 beta receptor type I (IL-1RI)/toll-like receptor type 4 (TLR4) signalling. The mechanism(s) by which ethanol activates these receptors in astroglial cells remains unknown. Recently, plasma membrane microdomains, lipid rafts, have been identified as platforms for receptor signalling and, in astrocytes, rafts/caveolae constitute an important integrators of signal events and trafficking. Here we show that stimulation of astrocytes with IL-1beta, lipopolysaccharide or ethanol (10 and 50 mM), triggers the translocation of IL-1RI and/or TLR4 into lipid rafts caveolae-enriched fractions, promoting the recruitment of signalling molecules (phospho-IL-1R-associated kinase and phospho-extracellular regulated-kinase) into these microdomains. With confocal microscopy, we further demonstrate that IL-1RI is internalized by caveolar endocytosis via enlarged caveosomes organelles upon IL-1beta or ethanol treatment, which sorted their IL-1RI cargo into the endoplasmic reticulum-Golgi compartment and into the nucleus of astrocytes. In short, our findings demonstrate that rafts/caveolae are critical for IL-1RI and TLR4 signalling in astrocytes, and reveal a novel mechanism by which ethanol, by interacting with lipid rafts caveolae, promotes IL-1RI and TLR4 receptors recruitment, triggering their endocytosis via caveosomes and downstream signalling stimulation. These results suggest that TLRs receptors are important targets of ethanol-induced inflammatory damage in the brain. |
| Databáze: | OpenAIRE |
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