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

doi:10.1038/ncomms13129

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

Department of Pediatrics

Research output: Contribution to journal › Article › peer-review

101 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 language	English
Article number	13129
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13129
Publication status	Published - 2016 Oct 25

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea Grants funded by the Korean Government (2013R1A2A2A01067985), and by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (2012M3A9B4028631, 2012M3A9C7050126, 2012M3A9C6049724 and 2015M3A9B6073856), and by the Ministry of Health & Welfare, Republic of Korea (HI15C0916).

Publisher Copyright:
© The Author(s) 2016.

All Science Journal Classification (ASJC) codes

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

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10.1038/ncomms13129

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Jang, J., Park, S., Jin Hur, H., Cho, H. J., Hwang, I., Pyo Kang, Y., Im, I., Lee, H., Lee, E., Yang, W., Kang, H. C., Won Kwon, S., Yu, J. W., & Kim, D. W. (2016). 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. Nature communications, 7, Article 13129. https://doi.org/10.1038/ncomms13129

@article{d64a0e4130644c00a9f1aa912cf92c61,

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}",

note = "Funding Information: This work was supported by the National Research Foundation of Korea Grants funded by the Korean Government (2013R1A2A2A01067985), and by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (2012M3A9B4028631, 2012M3A9C7050126, 2012M3A9C6049724 and 2015M3A9B6073856), and by the Ministry of Health & Welfare, Republic of Korea (HI15C0916). Publisher Copyright: {\textcopyright} The Author(s) 2016.",

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day = "25",

doi = "10.1038/ncomms13129",

language = "English",

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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

N1 - Funding Information: This work was supported by the National Research Foundation of Korea Grants funded by the Korean Government (2013R1A2A2A01067985), and by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (2012M3A9B4028631, 2012M3A9C7050126, 2012M3A9C6049724 and 2015M3A9B6073856), and by the Ministry of Health & Welfare, Republic of Korea (HI15C0916). Publisher Copyright: © The Author(s) 2016.

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.

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JO - Nature communications

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ER -

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

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