한빛사 논문
Abstract
Jiho Jang1,*, Sangjun Park2,*, Hye Jin Hur1, Hyun-Ju Cho1, Inhwa Hwang2, Yun Pyo Kang3, Isak Im1, Hyunji Lee1, Eunju Lee2, Wonsuk Yang1, Hoon-Chul Kang4, Sung Won Kwon3, Je-Wook Yu2,** & Dong-Wook Kim1,**
1 Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea. 2 Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea. 3 College of Pharmacy, Seoul National University, Seoul 08826, Korea. 4 Division of Pediatric Neurology, Department of Pediatrics, Severance Children’s Hospital, Epilepsy Research Institute, Seoul 03722, Korea.
* These authors contributed equally to this work.
** These authors jointly supervised this work.
Correspondence to Je-Wook Yu or Dong-Wook Kim.
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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