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

Proc Natl Acad Sci U S A. 2021 Apr 13;118(15):e2025847118. doi: 10.1073/pnas.2025847118.

Abstract

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.

Keywords: Alzheimer’s disease; Lewy body dementia; Parkinson’s disease; antibody therapies; neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / immunology
  • Antibodies / immunology
  • Cell Differentiation
  • Cells, Cultured
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Inflammasomes / metabolism*
  • Microglia / cytology
  • Microglia / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Parkinson Disease / immunology*
  • Toll-Like Receptor 2 / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / immunology*

Substances

  • Amyloid beta-Peptides
  • Antibodies
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • alpha-Synuclein