Abstract

BackgroundPrion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal disease-associated prion protein, PrPSc. In prion-infected brains, activated microglia are often present in the vicinity of PrPSc aggregates, and microglial activation is thought to play a key role in the pathogenesis of prion diseases. Although interleukin (IL)-1β release by prion-induced microglia has been widely reported, the mechanism by which primed microglia become activated and secrete IL-1β in prion diseases has not yet been elucidated. In this study, we investigated the role of the NACHT, LRR and PYD domains-containing protein (NALP)3 inflammasome in IL-1β release from lipopolysaccharide (LPS)-primed microglia after exposure to a synthetic neurotoxic prion fragment (PrP106-126).MethodsThe inflammasome components NALP3 and apoptosis-associated speck-like protein (ASC) were knocked down by gene silencing. IL-1β production was assessed using ELISA. The mRNA expression of NALP3, ASC, and pro-inflammatory factors was measured by quantitative PCR. Western blot analysis was used to detect the protein level of NALP3, ASC, caspase-1 and nuclear factor-κB.ResultsWe found that that PrP106-126-induced IL-1β release depends on NALP3 inflammasome activation, that inflammasome activation is required for the synthesis of pro-inflammatory and chemotactic factors by PrP106-126-activated microglia, that inhibition of NF-κB activation abrogated PrP106-126-induced NALP3 upregulation, and that potassium efflux and production of reactive oxygen species were implicated in PrP106-126-induced NALP3 inflammasome activation in microglia.ConclusionsWe conclude that the NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. To our knowledge, this is the first time that strong evidence for the involvement of NALP3 inflammasome in prion-associated inflammation has been found.

Highlights

  • Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal disease-associated prion protein, PrPSc

  • We investigated the role of the NALP3 inflammasome in PrP106-126-induced IL-1β release, and found that the NALP3-associated speck-like protein (ASC) inflammasome plays a key role in caspase-1 and IL-1β activation in microglia in response to PrP106-126 stimulation

  • PrP106-126-induced release of interleukin (IL)-1β requires the NALP3 inflammasome To elucidate the role of the NALP3 inflammasome in PrP106-126-induced microglial activation, we examined the role of the NALP3 inflammasome in PrP106-126-induced IL-1β release

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Summary

Introduction

Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal disease-associated prion protein, PrPSc. We investigated the role of the NACHT, LRR and PYD domains-containing protein (NALP) inflammasome in IL-1β release from lipopolysaccharide (LPS)-primed microglia after exposure to a synthetic neurotoxic prion fragment (PrP106-126). Known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders, characterized by brain vacuolation, neuronal cell death, and microgliosis [1]. They are caused by the conversion of cellular prion protein (PrPC) into the pathological isoform (PrPSc) through conformational changes. The accumulation of abnormal forms of prion protein (PrPSc) has been shown to be the main causative agent of these diseases [3]. PrP106-126 is commonly used as a model for the investigation of PrPSc neurotoxicity [4,5,6]

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