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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·2016·Nature Communications
DOI 10.1038/ncomms13129PMC PMC5093305
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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.

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  • Administration of 25-HC into the corpus callosum of mice induces potent proinflammatory activation of microglia, NLRP3 inflammasome-mediated neuroinflammation, IL-1β secretion, and cell death.

    “Ch25h was reported to be upregulated in patient-derived cells of X-linked adrenoleukodystrophy, and administration of 25-HC into the corpus callosum of mice induced potent proinflammatory activation of microglia, NLRP3 inflammasome-mediated neuroinflammation, interleukin 1 beta (IL-1β) secretion, and cell death (Jang et al., 2016).”

    From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Jang et al., 2016

  • CH25H deficient mice have decreased inflammatory-mediated pathology and death following influenza infection, reduced immune responses following experimental autoimmune encephalomyelitis (EAE), and in a mouse model of X-linked adrenoleukodystrophy (X-ALD).

    “CH25H deficient mice have also been shown to have decreased inflammatory-mediated pathology and death following influenza infection [80], reduced immune responses both following experimental autoimmune encephalomyelitis (EAE) [81] and in a mouse model of X-linked adrenoleukodystrophy (X-ALD) [82]”

    From 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner (2020) · cites this paper as [82]

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Metadata

Authors
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.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-10-25
Volume
7
Issue
1
ISSN
2041-1723
DOI
10.1038/ncomms13129
PMC
PMC5093305
Cited by
166
References
18
Language
en
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