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

• DOI: 10.1523/jneurosci.5282-06.2007
• Publication Date: 2007-02-21T18:59:09Z
• Authors: Michitaka Suzuki; Yuko Sugimoto; Yuki Ohsaki; Makoto Ueno; Shinsuke Kato; Yukisato Kitamura; Hiroshi Hosokawa; Joanna P. Davies; Yiannis A. Ioannou; Marie T. Vanier; Kousaku Ohno; Haruaki Ninomiya
• Keywords: Mice, Knockout; 0301 basic medicine; Interleukin-6; Interleukin-8; Longevity; Brain; Niemann-Pick Disease, Type C; Endosomes; Interferon-beta; Fibroblasts; Culture Media; Toll-Like Receptor 4; Mice; STAT Transcription Factors; 03 medical and health sciences; Animals; Cytokines; Humans; Neuroglia; Cells, Cultured

Niemann–Pick disease type C (NPC) is an inherited lipid storage disorder caused by mutations in NPC1 or NPC2 genes. Loss of function either protein results the endosomal accumulation cholesterol and other lipids, progressive neurodegeneration, robust glial cell activation. Here, we report that cultured human NPC fibroblasts secrete interferon-β, interleukin-6 (IL-6), IL-8, contain increased levels signal transducers activators transcription (STATs). These cells also contained Toll-like receptor 4 (TLR4) accumulated cholesterol-enriched endosomes/lysosomes, small interfering RNA knockdown this reduced cytokine secretion. In −/− mouse brain, expressed TLR4 IL-6, whereas both neuronal STATs. Genetic deletion mice IL-6 secretion but failed to alter STAT activation brain. contrast, genetic normalized suppressed findings indicate constitutive leads STATs partly TLR4. suggest similar signaling events may underlie