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

Collection with item attached
2016
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/473416.do
DOI
10.1038/ncomms13129
Title
25-hydroxycholesterol contributes to cerebral inflammation of X-linkedadrenoleukodystrophy through activation of the NLRP3 inflammasome
Description
This work was supported by the National Research Foundation of KoreaGrants funded by the Korean Government (2013R1A2A2A01067985), and by theBio & Medical Technology Development Program of the NRF funded by theKorean government, MSIP (2012M3A9B4028631, 2012M3A9C7050126,2012M3A9C6049724 and 2015M3A9B6073856), and by the Ministry of Health &Welfare, Republic of Korea (HI15C0916). We thank Dong-Su Jang, MFA,(Medical Illustrator, Medical Research Support Section, YonseiUniversity College of Medicine) for his help with the illustrations.
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-1 beta 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.
provenance
Made available in Cube on 2018-09-28T10:18:56Z (GMT). No. of bitstreams: 0
language
English
author
Jang, Jiho
Park, Sangjun
Hur, Hye Jin
Cho, Hyun-Ju
Hwang, Inhwa
Kang, Yun Pyo
Im, Isak
Lee, Hyunji
Lee, Eunju
Yang, Wonsuk
Kang, Hoon-Chul
Kwon, Sung Won
Yu, Je-Wook
Kim, Dong-Wook
accessioned
2018-09-28T10:18:56Z
available
2018-09-28T10:18:56Z
issued
2016
citation
NATURE COMMUNICATIONS(7)
issn
2041-1723
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/473416.do
Funder
교육부
Funding Program
BK21플러스사업(0.5)
Project ID
1345258242
Jurisdiction
Rep.of Korea
Project Name
Research & Educational Program for Creative Global Pharmaceutical Scientists (R&E Program for CGPS)
rights
openAccess
type
article


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