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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  ;  Dong-Wook Kim 
 NATURE COMMUNICATIONS, Vol.7 : 13129, 2016 
Journal Title
Issue Date
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.
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1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kim, Dong Wook(김동욱) ORCID logo https://orcid.org/0000-0002-5025-1532
Yang, Won Suk(양원석)
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
Jang, Ji Ho(장지호) ORCID logo https://orcid.org/0000-0001-5551-3514
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