Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia.

Autor:	Trudler D; 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., Nazor KL; MYi Diagnostics & Discovery, San Diego, CA 92121., Eisele YS; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15219., Grabauskas T; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037., Dolatabadi N; 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., Parker J; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121., Sultan A; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121., Zhong Z; 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., Goodwin MS; 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., Levites Y; 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., Golde TE; 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., Kelly JW; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037., Sierks MR; Department of Chemical Engineering, Arizona State University, Tempe, AZ 85287., Schork NJ; 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., Karin M; Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093; mkarin@ucsd.edu rajesh@scintillon.edu slipton@scripps.edu.; Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA 92093., Ambasudhan R; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037; mkarin@ucsd.edu rajesh@scintillon.edu slipton@scripps.edu.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121., Lipton SA; Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037; mkarin@ucsd.edu rajesh@scintillon.edu slipton@scripps.edu.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121.; 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.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Apr 13; Vol. 118 (15).
DOI:	10.1073/pnas.2025847118
Abstrakt:	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. Competing Interests: Competing interest statement: S.A.L. and G.H. are coauthors on a published consensus statement review of cell-death criteria along with several dozen other authors who are authorities in this field [N. M. C. Connolly et al., Cell Death Differ. 25, 542–572 (2018)]. That manuscript was published in order to help nonexperts in the field understand and use criteria for various types of cell death. They also published a similar type of review paper together 10 y ago [G. E. Hardingham, S. A. Lipton, Antioxid. Redox Signal. 14, 1421–1424 (2011)]. However, S.A.L. and G.H. have never formally collaborated or worked together on any laboratory-based scientific project, including the current work.
Databáze:	MEDLINE
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