Soluble {alpha}-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia [Neuroscience],Proceedings of the National Academy of Sciences of the United States of America

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Soluble {alpha}-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia [Neuroscience]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-04-13 , DOI: 10.1073/pnas.2025847118
Dorit Trudler _{1,

2,

3} , Kristopher L Nazor ₄ , Yvonne S Eisele _{5,

6} , Titas Grabauskas _{1,

2} , Nima Dolatabadi _{1,

2,

3} , James Parker ₃ , Abdullah Sultan ₃ , Zhenyu Zhong _{7,

8,

9} , Marshall S Goodwin _{10,

11,

12} , Yona Levites _{10,

11,

12} , Todd E Golde _{10,

11,

12} , Jeffery W Kelly _{1,

2,

5} , Michael R Sierks ₁₃ , Nicholas J Schork _{14,

15,

16,

17} , Michael Karin _{8,

18} , Rajesh Ambasudhan _{2,

3,

19} , Stuart A Lipton _{2,

3,

19,

20,

21}

Affiliation

Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.
MYi Diagnostics & Discovery, San Diego, CA 92121.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15219.
Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093.
Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA 92093.
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610.
Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610.
McKnight Brain Institute, University of Florida, Gainesville, FL 32610.
Department of Chemical Engineering, Arizona State University, Tempe, AZ 85287.
Quantitative Medicine & Systems Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004.
Department of Psychiatry, University of California San Diego, La Jolla, CA 92037.
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92037.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.
Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093;
Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037;
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037.
Department of Neurosciences, University of California San Diego School of Medicine, La Jolla, CA 92093.

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.

中文翻译：

可溶性 {alpha}-突触核蛋白-抗体复合物激活 hiPSC 衍生的小胶质细胞中的 NLRP3 炎性体 [神经科学]

帕金森病的特征是 α-突触核蛋白 (αSyn) 的积累。从受损神经元中释放寡聚/纤维状 αSyn 可能通过小胶质细胞激活部分加剧神经元死亡。迄今为止，仍不清楚寡聚/纤维状 αSyn 是否可以激活人小胶质细胞中的核苷酸结合寡聚化结构域 (NOD) 样受体 (NLR) 家族含热蛋白结构域 3 (NLRP3) 炎性体，以及抗 αSyn 抗体是否可以阻止这种效应. 在这里，我们表明 αSyn 通过涉及 Toll 样受体 2 (TLR2) 参与和线粒体损伤的双重刺激激活人诱导多能干细胞 (hiPSC) 衍生的小胶质细胞 (hiMG) 中的 NLRP3 炎性体。在体外，hiMG 可以被 hiPSC 衍生的 A9-多巴胺能神经元分泌的突变体 (A53T) αSyn 激活。出奇，αSyn-抗体复合物增强而不是抑制炎症小体介导的白细胞介素-1β (IL-1β) 分泌，表明这些复合物在人类环境中是神经炎症性的。添加低聚淀粉样蛋白-β 肽 (Aβ) 及其同源抗体后，观察到炎症进一步增加。在体内，将 hiMG 与 αSyn 植入人源化小鼠脑中会导致 caspase-1 激活和神经毒性，αSyn 抗体会加剧这种情况。这些发现可能对旨在消除人脑中错误折叠/聚集的蛋白质的抗体疗法具有重要意义，因为它们可能会自相矛盾地引发人类小胶质细胞的炎症。添加低聚淀粉样蛋白-β 肽 (Aβ) 及其同源抗体后，观察到炎症进一步增加。在体内，将 hiMG 与 αSyn 植入人源化小鼠脑中会导致 caspase-1 激活和神经毒性，αSyn 抗体会加剧这种情况。这些发现可能对旨在消除人脑中错误折叠/聚集的蛋白质的抗体疗法具有重要意义，因为它们可能会自相矛盾地引发人类小胶质细胞的炎症。添加低聚淀粉样蛋白-β 肽 (Aβ) 及其同源抗体后，观察到炎症进一步增加。在体内，将 hiMG 与 αSyn 植入人源化小鼠脑中会导致 caspase-1 激活和神经毒性，αSyn 抗体会加剧这种情况。这些发现可能对旨在消除人脑中错误折叠/聚集的蛋白质的抗体疗法具有重要意义，因为它们可能会自相矛盾地引发人类小胶质细胞的炎症。

更新日期：2021-04-09

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