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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish (US)
Article number13129
JournalNature Communications
Volume7
DOIs
StatePublished - Oct 25 2016

Fingerprint

Adrenoleukodystrophy
Inflammasomes
fatty acids
Chemical activation
activation
Inflammation
interleukins
efflux
stem cells
cholesterol
fibroblasts
mutations
liver
death
brain
mice
potassium
Fatty Acids
assembly
disorders

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. / Jang, Jiho; Park, Sangjun; Jin Hur, Hye; Cho, Hyun Ju; Hwang, Inhwa; Pyo Kang, Yun; Im, Isak; Lee, Hyunji; Lee, Eunju; Yang, Wonsuk; Kang, Hoon Chul; Won Kwon, Sung; Yu, Je Wook; Kim, Dong Wook.

In: Nature Communications, Vol. 7, 13129, 25.10.2016.

Research output: Contribution to journalArticle

Jang, J, Park, S, Jin Hur, H, Cho, HJ, Hwang, I, Pyo Kang, Y, Im, I, Lee, H, Lee, E, Yang, W, Kang, HC, Won Kwon, S, Yu, JW & Kim, DW 2016, '25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome', Nature Communications, vol. 7, 13129. https://doi.org/10.1038/ncomms13129
Jang, Jiho ; Park, Sangjun ; Jin Hur, Hye ; Cho, Hyun Ju ; Hwang, Inhwa ; Pyo Kang, Yun ; Im, Isak ; Lee, Hyunji ; Lee, Eunju ; Yang, Wonsuk ; Kang, Hoon Chul ; Won Kwon, Sung ; Yu, Je Wook ; Kim, Dong Wook. / 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. In: Nature Communications. 2016 ; Vol. 7.
@article{6dbd22613e944966a2e6e18ef0e8bbb6,
title = "25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome",
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.",
author = "Jiho Jang and Sangjun Park and {Jin Hur}, Hye and Cho, {Hyun Ju} and Inhwa Hwang and {Pyo Kang}, Yun and Isak Im and Hyunji Lee and Eunju Lee and Wonsuk Yang and Kang, {Hoon Chul} and {Won Kwon}, Sung and Yu, {Je Wook} and Kim, {Dong Wook}",
year = "2016",
month = "10",
day = "25",
doi = "10.1038/ncomms13129",
language = "English (US)",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome

AU - Jang, Jiho

AU - Park, Sangjun

AU - Jin Hur, Hye

AU - Cho, Hyun Ju

AU - Hwang, Inhwa

AU - Pyo Kang, Yun

AU - Im, Isak

AU - Lee, Hyunji

AU - Lee, Eunju

AU - Yang, Wonsuk

AU - Kang, Hoon Chul

AU - Won Kwon, Sung

AU - Yu, Je Wook

AU - Kim, Dong Wook

PY - 2016/10/25

Y1 - 2016/10/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84992200597&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992200597&partnerID=8YFLogxK

U2 - 10.1038/ncomms13129

DO - 10.1038/ncomms13129

M3 - Article

C2 - 27779191

AN - SCOPUS:84992200597

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 13129

ER -