Endosomal Accumulation of Toll-Like Receptor 4 Causes Constitutive Secretion of Cytokines and Activation of Signal Transducers and Activators of Transcription in Niemann–Pick Disease Type C (NPC) Fibroblasts: A Potential Basis for Glial Cell Activation in the NPC Brain
Open Access
- 21 February 2007
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 27 (8) , 1879-1891
- https://doi.org/10.1523/jneurosci.5282-06.2007
Abstract
Niemann–Pick disease type C (NPC) is an inherited lipid storage disorder caused by mutations in NPC1 or NPC2 genes. Loss of function of either protein results in the endosomal accumulation of cholesterol and other lipids, progressive neurodegeneration, and robust glial cell activation. Here, we report that cultured human NPC fibroblasts secrete interferon-β, interleukin-6 (IL-6), and IL-8, and contain increased levels of signal transducers and activators of transcription (STATs). These cells also contained increased levels of Toll-like receptor 4 (TLR4) that accumulated in cholesterol-enriched endosomes/lysosomes, and small interfering RNA knockdown of this receptor reduced cytokine secretion. In the NPC1−/− mouse brain, glial cells expressed TLR4 and IL-6, whereas both glial and neuronal cells expressed STATs. Genetic deletion of TLR4 in NPC1−/− mice reduced IL-6 secretion by cultured fibroblasts but failed to alter STAT levels or glial cell activation in the brain. In contrast, genetic deletion of IL-6 normalized STAT levels and suppressed glial cell activation. These findings indicate that constitutive cytokine secretion leads to activation of STATs in NPC fibroblasts and that this secretion is partly caused by an endosomal accumulation of TLR4. These results also suggest that similar signaling events may underlie glial cell activation in the NPC1−/− mouse brain.Keywords
This publication has 43 references indexed in Scilit:
- Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann‐Pick C miceJournal of Neuroscience Research, 2005
- Deregulation of the Phosphatidylinositol-3 Kinase Signaling Cascade Is Associated with Neurodegeneration in Npc1−/− Mouse BrainThe American Journal of Pathology, 2005
- Consequences of NPC1 and NPC2 loss of function in mammalian neuronsBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2004
- Toll-like receptor signallingNature Reviews Immunology, 2004
- Lysines 128 and 132 Enable Lipopolysaccharide Binding to MD-2, Leading to Toll-like Receptor-4 Aggregation and Signal TransductionJournal of Biological Chemistry, 2003
- Niemann–Pick type C disease: Accelerated neurofibrillary tangle formation and amyloid β deposition associated with apolipoprotein E ε4 homozygosityAnnals of Neurology, 2002
- Studies on neuronal death in the mouse model of Niemann‐Pick C diseaseJournal of Neuroscience Research, 2002
- Microglial activation and amyloid‐β clearance induced by exogenous heat‐shock proteinsThe FASEB Journal, 2002
- Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblastsJournal of Medical Genetics, 2000
- STATs: Signal Transducers and Activators of TranscriptionPublished by Elsevier ,1996