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The NLRP3-Caspase 1 Inflammasome Negatively Regulates Autophagy via TLR4-TRIF in Prion Peptide-Infected Microglia

Overview of attention for article published in Frontiers in Aging Neuroscience, April 2018
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Title
The NLRP3-Caspase 1 Inflammasome Negatively Regulates Autophagy via TLR4-TRIF in Prion Peptide-Infected Microglia
Published in
Frontiers in Aging Neuroscience, April 2018
DOI 10.3389/fnagi.2018.00116
Pubmed ID
Authors

Mengyu Lai, Hao Yao, Syed Zahid Ali Shah, Wei Wu, Di Wang, Ying Zhao, Lu Wang, Xiangmei Zhou, Deming Zhao, Lifeng Yang

Abstract

Prion diseases are neurodegenerative disorders characterized by the accumulation of misfolded prion protein, spongiform changes in the brain, and brain inflammation as a result of the wide-spread activation of microglia. Autophagy is a highly conserved catabolic process for the clearance of cytoplasmic components, including protein aggregates and damaged organelles; this process also eliminates pathological PrPSc as it accumulates during prion infection. The NALP3 inflammasome is a multiprotein complex that is a component of the innate immune system and is responsible for the release of pro-inflammatory cytokines. Our previous study showed that the neurotoxic prion peptide PrP106-126 induces NALP3 inflammasome activation and subsequent IL-1β release in microglia. Autophagy is involved in the regulation of the immune responses and inflammation in many diseases including neurodegenerative diseases. However, the relationship between autophagy and NALP3 inflammasome in prion diseases has not been investigated. In this study, we demonstrated that the processing and release of mature IL-1β is significantly enhanced by the inhibition of autophagy. Conversely, gene-silencing of the NALP3 inflammasome promotes autophagy. Suppression of TRIF or TLR4 by siRNA attenuated PrP106-126-induced autophagy, which is indicating that the TLR4-TRIF signaling pathway is involved in PrP106-26-induced autophagy. Caspase 1 directly cleaved TRIF to diminish TLR-4-TRIF mediated autophagy. Our findings suggest that the inhibition of autophagy by NALP3 inflammasome is probably mediated by activated Caspase-1-induced TRIF cleavage. This is the first study reporting that the NALP3 inflammasome complex negatively regulates autophagy in response to PrP106-126 stimulation in microglia, and partly explains the mechanism of autophagy inhibition by Caspase-1 in PrP106-126-induced BV2 cell activation. Our findings suggest that autophagy up-regulation and inhibition of Caspase-1 may protect against prion-induced neuroinflammation and accelerate misfolded protein degradation and are potential therapeutic approaches for prion diseases.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 42 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 42 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 7 17%
Student > Bachelor 7 17%
Researcher 7 17%
Student > Master 4 10%
Student > Doctoral Student 2 5%
Other 4 10%
Unknown 11 26%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 13 31%
Neuroscience 7 17%
Agricultural and Biological Sciences 5 12%
Immunology and Microbiology 3 7%
Medicine and Dentistry 1 2%
Other 3 7%
Unknown 10 24%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 05 May 2018.
All research outputs
#13,592,375
of 23,045,021 outputs
Outputs from Frontiers in Aging Neuroscience
#3,002
of 4,855 outputs
Outputs of similar age
#169,597
of 327,293 outputs
Outputs of similar age from Frontiers in Aging Neuroscience
#84
of 113 outputs
Altmetric has tracked 23,045,021 research outputs across all sources so far. This one is in the 39th percentile – i.e., 39% of other outputs scored the same or lower than it.
So far Altmetric has tracked 4,855 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 13.2. This one is in the 36th percentile – i.e., 36% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 327,293 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 113 others from the same source and published within six weeks on either side of this one. This one is in the 24th percentile – i.e., 24% of its contemporaries scored the same or lower than it.