Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
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.
Nat Commun. 2016 Oct 25;7:13129. doi: 10.1038/ncomms13129.
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.
X 连锁肾上腺脑白质营养不良（X-ALD）是一种渐进性神经退行性疾病，与极长链脂肪酸（VLCFA）的积累有关。ABCD1 突变引起的 X 连锁肾上腺脑白质营养不良（X-ALD），是一种渐进性神经退行性疾病，与极长链脂肪酸（VLCFA）的积累有关。大脑炎症性脱髓鞘是儿童脑肾上腺脑白质营养不良（CCALD）的主要特征，也是 ALD 最严重的形式，但它的潜在机制仍不清楚。在这里，我们根据对 ALD 患者来源的诱导多能干细胞和体外成纤维细胞的分析，确定了胆固醇 25-羟化酶（CH25H）和 25-羟胆固醇（25-HC）在 CCALD 的细胞环境中的异常产生。有趣的是，25-HC 而不是 VLCFA 通过钾流出、线粒体活性氧（ROS）和肝 X 受体（LXR）介导的途径促进 NRLP3 炎性小体的组装和激活。此外，25-HC 立体定向注射到小鼠大脑胼胝体中，以 NLRP3 炎性小体依赖性方式诱导小胶质细胞募集、白细胞介素-1β产生和少突胶质细胞死亡。总之，我们的结果表明，25-HC 通过激活 NLRP3 炎性小体介导 X-ALD 的神经炎症。
