Prion Pathogenesis in the Absence of NLRP3/ASC Inflammasomes

Sorce, Silvia; Schwarz, Petra; Aguzzi, Adriano

doi:10.1371/journal.pone.0117208

Cited by 37 publications

(32 citation statements)

References 72 publications

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“…The microglial characteristics during the early stages of CNS prion disease are instead similar to the anti-inflammatory profile exhibited by macrophages following their engulfment of apoptotic cells [ 171 ]. This is consistent with data showing that CNS prion disease is unaltered in the steady state in mice lacking the NLRP3 inflammasome [ 172 ] (essential for release of IL-1β), NF-κB signalling [ 173 ] or MyD88 signalling [ 174 ]. Treatment of scrapie-affected sheep with the glucocorticoid dexamethasone during the clinical phase similarly had no effect on the development of neuropathology [ 175 ].…”

Section: Cns Prion Diseasesupporting

confidence: 91%

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

Mabbott

Bradford

Pal

et al. 2020

IJMS

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Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.

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Section: Cns Prion Diseasesupporting

confidence: 91%

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

Mabbott

Bradford

Pal

et al. 2020

IJMS

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“…In a recently published work, Nuvolone et al (2014) demonstrated that NALP3 and ASC have limited role in prion pathogenesis in vivo model with RML6 strain. This might be due to strain dependent differences in prion infections.…”

Section: Discussionmentioning

confidence: 99%

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

Lai

Yao

Shah

et al. 2018

Front. Aging Neurosci.

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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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“…Additionally, the absence of NLRP3 or ASC did not significantly change levels of IL-1β in the brain at the terminal stage of the disease. Thus, based on existing data, NLRP3 and ASC do not play significant roles in prion pathogenesis (89).…”

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E N mentioning

confidence: 97%

Microglia in prion diseases

Aguzzi

Zhu

2017

Journal of Clinical Investigation

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Prion Pathogenesis in the Absence of NLRP3/ASC Inflammasomes

Cited by 37 publications

References 72 publications

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

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

Microglia in prion diseases

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