25-hydroxycholesterol Contributes to Cerebral Inflammation of X-linked Adrenoleukodystrophy Through Activation of the NLRP3 Inflammasome

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Oct 26

PMID 27779191

Citations 73

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Effects of acute pro-inflammatory stimulation and 25-hydroxycholesterol on hippocampal plasticity and learning involve NLRP3 inflammasome and cellular stress responses.

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A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.

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