25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome

Jiho Jang, Sangjun Park, Hye Jin Hur, Hyun-Ju Cho, Inhwa Hwang, Yun Pyo Kang, Isak Im, Hyunji Lee, Eunju Lee, Wonsuk Yang, Hoon-Chul Kang, Sung Won Kwon, Je-Wook Yu () and Dong-Wook Kim ()
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Jiho Jang: Yonsei University College of Medicine
Sangjun Park: Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine
Hye Jin Hur: Yonsei University College of Medicine
Hyun-Ju Cho: Yonsei University College of Medicine
Inhwa Hwang: Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine
Yun Pyo Kang: College of Pharmacy, Seoul National University
Isak Im: Yonsei University College of Medicine
Hyunji Lee: Yonsei University College of Medicine
Eunju Lee: Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine
Wonsuk Yang: Yonsei University College of Medicine
Hoon-Chul Kang: Severance Children’s Hospital, Epilepsy Research Institute
Sung Won Kwon: College of Pharmacy, Seoul National University
Je-Wook Yu: Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine
Dong-Wook Kim: Yonsei University College of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract X-linked adrenoleukodystrophy (X-ALD), caused by an ABCD1 mutation, is a progressive neurodegenerative disorder associated with the accumulation of very long-chain fatty acids (VLCFA). Cerebral inflammatory demyelination is the major feature of childhood cerebral ALD (CCALD), the most severe form of ALD, but its underlying mechanism remains poorly understood. Here, we identify the aberrant production of cholesterol 25-hydroxylase (CH25H) and 25-hydroxycholesterol (25-HC) in the cellular context of CCALD based on the analysis of ALD patient-derived induced pluripotent stem cells and ex vivo fibroblasts. Intriguingly, 25-HC, but not VLCFA, promotes robust NLRP3 inflammasome assembly and activation via potassium efflux-, mitochondrial reactive oxygen species (ROS)- and liver X receptor (LXR)-mediated pathways. Furthermore, stereotaxic injection of 25-HC into the corpus callosum of mouse brains induces microglial recruitment, interleukin-1β production, and oligodendrocyte cell death in an NLRP3 inflammasome-dependent manner. Collectively, our results indicate that 25-HC mediates the neuroinflammation of X-ALD via activation of the NLRP3 inflammasome.

Date: 2016
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DOI: 10.1038/ncomms13129

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