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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 15; pp. 1 - 8
• Main Authors: Trudler, Dorit, Nazor, Kristopher L., Eisele, Yvonne S., Grabauskas, Titas, Dolatabadi, Nima, Parker, James, Sultan, Abdullah, Zhong, Zhenyu, Goodwin, Marshall S., Levites, Yona, Golde, Todd E., Kelly, Jeffery W., Sierks, Michael R., Schork, Nicholas J., Karin, Michael, Ambasudhan, Rajesh, Lipton, Stuart A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.04.2021
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - immunology; Amyloid beta-Peptides - immunology; Antibodies; Antibodies - immunology; Biological Sciences; Brain; Caspase-1; Cell Differentiation; Cells, Cultured; Damage accumulation; Domains; Dopamine receptors; Humans; IL-1β; Immunotherapy; Induced Pluripotent Stem Cells - cytology; Inflammasomes; Inflammasomes - metabolism; Inflammation; Interleukins; Microglia; Microglia - cytology; Microglia - immunology; Mitochondria; Movement disorders; Neurodegenerative diseases; Neurons; Neurotoxicity; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Nucleotides; Oligomerization; Parkinson Disease - immunology; Parkinson's disease; Pluripotency; Pyrin protein; Receptors; Stem cells; Synuclein; TLR2 protein; Toll-Like Receptor 2 - metabolism; Toll-like receptors; β-Amyloid; antibody therapies; Alzheimer’s disease; neuroinflammation; Parkinson’s disease; Lewy body dementia
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2025847118

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.