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| DOI | 10.1073/pnas.2025847118 |
| Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia | |
| Trudler D.; Nazor K.L.; Eisele Y.S.; Grabauskas T.; Dolatabadi N.; Parker J.; Sultan A.; Zhong Z.; Goodwin M.S.; Levites Y.; Golde T.E.; Kelly J.W.; Sierks M.R.; Schork N.J.; Karin M.; Ambasudhan R.; Lipton S.A. | |
| 发表日期 | 2021 |
| ISSN | 00278424 |
| 卷号 | 118期号:15 |
| 英文摘要 | Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia. © 2021 National Academy of Sciences. All rights reserved. |
| 英文关键词 | Alzheimer's disease; Antibody therapies; Lewy body dementia; Neuroinflammation; Parkinson's disease |
| 语种 | 英语 |
| 来源期刊 | Proceedings of the National Academy of Sciences of the United States of America
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| 文献类型 | 期刊论文 |
| 条目标识符 | http://gcip.llas.ac.cn/handle/2XKMVOVA/179920 |
| 作者单位 | Neurodegeneration New Medicines Center, The Scripps Research Institute, San Diego, CA 92037, United States; Department of Molecular Medicine, The Scripps Research Institute, San Diego, CA 92037, United States; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, United States; MYi Diagnostics & Discovery, San Diego, CA 92121, United States; Department of Chemistry, The Scripps Research Institute, San Diego, CA 92037, United States; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, United States; Department of Pharmacology, University of California San Diego, School of Medicine, San Diego, CA 92093, United States; Department of Pathology, University of California San Diego, School of Medicine, San Diego, CA 92093, United States; Department of Immunology, University of Texas, Southwestern Medical Center, Dallas, TX 75390, United States; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610... |
| 推荐引用方式 GB/T 7714 | Trudler D.,Nazor K.L.,Eisele Y.S.,et al. Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia[J],2021,118(15). |
| APA | Trudler D..,Nazor K.L..,Eisele Y.S..,Grabauskas T..,Dolatabadi N..,...&Lipton S.A..(2021).Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia.Proceedings of the National Academy of Sciences of the United States of America,118(15). |
| MLA | Trudler D.,et al."Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia".Proceedings of the National Academy of Sciences of the United States of America 118.15(2021). |
| 条目包含的文件 | 条目无相关文件。 | |||||
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