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.
authors: Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
authors: Jiho
authors: J
authors: Jang
authors: 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.
authors: Sangjun
authors: S
authors: Park
authors: Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
authors: Hye
authors: H
authors: Jin Hur
authors: Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
authors: Hyun-Ju
authors: HJ
authors: Cho
authors: 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.
authors: Inhwa
authors: I
authors: Hwang
authors: College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors: Yun
authors: Y
authors: Pyo Kang
authors: Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
authors: Isak
authors: I
authors: Im
authors: Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
authors: Hyunji
authors: H
authors: Lee
authors: 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.
authors: Eunju
authors: E
authors: Lee
authors: Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
authors: Wonsuk
authors: W
authors: Yang
authors: Division of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Epilepsy Research Institute, Seoul 03722, Korea.
authors: Hoon-Chul
authors: HC
authors: Kang
authors: College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors: Sung
authors: S
authors: Won Kwon
authors: 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.
authors: Je-Wook
authors: JW
authors: Yu
authors: Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
authors: Dong-Wook
authors: DW
authors: Kim
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1 / Q000235:genetics / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003337:Corpus Callosum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology*; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation; D007276:Injections, Intraventricular; D000071518:Liver X Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D013238:Stereotaxic Techniques; D013250:Steroid Hydroxylases / Q000172:deficiency / Q000235:genetics; D066127:White Matter / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D006888:Hydroxycholesterols; D058847:Inflammasomes; D000071518:Liver X Receptors; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; C007997:25-hydroxycholesterol; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase