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

Abstract : 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.
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https://hal-cea.archives-ouvertes.fr/cea-03344484
Contributor : Ronald Melki Connect in order to contact the contributor
Submitted on : Thursday, September 16, 2021 - 2:25:02 PM
Last modification on : Saturday, September 18, 2021 - 3:31:27 AM

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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, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, inPress, ⟨10.4049/jimmunol.2100035⟩. ⟨cea-03344484⟩

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