The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation

Background: prion 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).methods: the 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.results: we 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.conclusions: we 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. © 2012 shi et al.; licensee biomed central ltd.