Microglial NLRP3 inflammasome activation upon TLR2 and TLR5 ligation by distinct $\alpha$-synuclein assemblies

Hannah Scheiblich (1) , Luc Bousset (2) , Stephanie Schwartz (1) , Angelika Griep , Eicke Latz , Ronald Melki (2, 3) , Michael T Heneka

1 Universität Bonn = University of Bonn
2 CNRS - Centre National de la Recherche Scientifique
3 MIRCEN - Molecular Imaging Research Center [Fontenay-aux-Roses]

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder characterized by the formation of cellular inclusions inside neurons that are rich in an abnormal form of the protein $\alpha$-synuclein ($\alpha$-syn). Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of signaling transduction pathways. Here, we studied microglial activation by distinct $\alpha$-syn forms and their clearance. Internalization of $\alpha$-syn monomers and oligomers efficiently activated the NLRP3 inflammasome via Toll-like receptor-2 and -5 ligation, thereby acting on different signaling checkpoints. We found that primary microglia effectively engulf $\alpha$-syn, but hesitate in its degradation. NLRP3 inhibition by the selective inhibitor CRID3 and NLRP3 deficiency improved the overall clearance of $\alpha$-syn oligomers. Together, these data show that distinct $\alpha$-syn forms exert different microglial NLRP3 inflammasome activation properties, thereby compromising its degradation which can be prevented by NLRP3 inhibition.

Mots clés: Microglia; NLRP3 inflammasome; Alpha-synuclein; Toll-like receptors; clearance

Domaines: Neurosciences [q-bio.NC]

Hannah Scheiblich, Luc Bousset, Stephanie Schwartz, Angelika Griep, Eicke Latz, et al.. Microglial NLRP3 inflammasome activation upon TLR2 and TLR5 ligation by distinct $\alpha$-synuclein assemblies. Journal of Immunology, In press, ⟨10.4049/jimmunol.2100035⟩. ⟨cea-03344484⟩