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Fyn kinase regulates misfolded ?-synuclein uptake and NLRP3 inflammasome activation in microglia.

ABSTRACT: Persistent microglia-mediated neuroinflammation is a major pathophysiological contributor to the progression of Parkinson's disease (PD), but the cell-signaling mechanisms governing chronic neuroinflammation are not well understood. Here, we show that Fyn kinase, in conjunction with the class B scavenger receptor CD36, regulates the microglial uptake of aggregated human ?-synuclein (?Syn), which is the major component of PD-associated Lewy bodies. ?Syn can effectively mediate LPS-independent priming and activation of the microglial NLRP3 inflammasome. Fyn kinase regulates both of these processes; it mediates PKC?-dependent NF-?B-p65 nuclear translocation, leading to inflammasome priming, and facilitates ?Syn import into microglia, contributing to the generation of mitochondrial reactive oxygen species and consequently to inflammasome activation. In vivo experiments using A53T and viral-?Syn overexpression mouse models as well as human PD neuropathological results further confirm the role of Fyn in NLRP3 inflammasome activation. Collectively, our study identifies a novel Fyn-mediated signaling mechanism that amplifies neuroinflammation in PD.

SUBMITTER: Panicker N

PROVIDER: S-EPMC6547864 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia.

Panicker Nikhil N Sarkar Souvarish S Harischandra Dilshan S DS Neal Matthew M Kam Tae-In TI Jin Huajun H Saminathan Hariharan H Langley Monica M Charli Adhithiya A Samidurai Manikandan M Rokad Dharmin D Ghaisas Shivani S Pletnikova Olga O Dawson Valina L VL Dawson Ted M TM Anantharam Vellareddy V Kanthasamy Anumantha G AG Kanthasamy Arthi A

The Journal of experimental medicine 20190429 6

Persistent microglia-mediated neuroinflammation is a major pathophysiological contributor to the progression of Parkinson's disease (PD), but the cell-signaling mechanisms governing chronic neuroinflammation are not well understood. Here, we show that Fyn kinase, in conjunction with the class B scavenger receptor CD36, regulates the microglial uptake of aggregated human α-synuclein (αSyn), which is the major component of PD-associated Lewy bodies. αSyn can effectively mediate LPS-independent pri ...[more]

PMID: 31036561

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Project description:BackgroundInterleukin-1? (IL-1?) is one of the most important cytokine secreted by activated microglia as it orchestrates the vicious cycle of inflammation by inducing the expression of various other pro-inflammatory cytokines along with its own production. Microglia-mediated IL-1? production is a tightly regulated mechanism which involves the activation of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome pathway. Our previous study suggests the critical role of heat shock protein 60 (HSP60) in IL-1?-induced inflammation in microglia through TLR4-p38 MAPK axis. However, whether HSP60 regulates endogenous IL-1? production is not known. Therefore, to probe the underlying mechanism, we elucidate the role of HSP60 in endogenous IL-1? production.MethodsWe used in vitro (N9 murine microglial cells) and in vivo (BALB/c mouse) models for our study. HSP60 overexpression and knockdown experiment was done to elucidate the role of HSP60 in endogenous IL-1? production by microglia. Western blotting and quantitative real-time PCR was performed using N9 cells and BALB/c mice brain, to analyze various proteins and transcript levels. Reactive oxygen species levels and mitochondrial membrane depolarization in N9 cells were analyzed by flow cytometry. We also performed caspase-1 activity assay and enzyme-linked immunosorbent assay to assess caspase-1 activity and IL-1? production, respectively.ResultsHSP60 induces the phosphorylation and nuclear localization of NF-?B both in vitro and in vivo. It also induces perturbation in mitochondrial membrane potential and enhances reactive oxygen species (ROS) generation in microglia. HSP60 further activates NLRP3 inflammasome by elevating NLRP3 expression both at RNA and protein levels. Furthermore, HSP60 enhances caspase-1 activity and increases IL-1? secretion by microglia. Knockdown of HSP60 reduces the IL-1?-induced production of IL-1? both in vitro and in vivo. Also, we have shown for the first time that knockdown of HSP60 leads to decreased IL-1? production during Japanese encephalitis virus (JEV) infection, which eventually leads to decreased inflammation and increased survival of JEV-infected mice.ConclusionHSP60 mediates microglial IL-1? production by regulating NLRP3 inflammasome pathway and reduction of HSP60 leads to reduction of inflammation in JEV infection.

Dataset Information

Fyn kinase regulates misfolded ?-synuclein uptake and NLRP3 inflammasome activation in microglia.

Publications

Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia.

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