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Prion replication sensitizes neurons to proinflammatory cytokines
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International audience. Background: Activation of glia in prion diseases contributes to TSE pathogenesis through the release of chemokines and pro-inflammatory cytokines acting as neurotoxic mediators. While it is now established that expression of the cellular prion protein (PrPC) at the surface of neuronal cells is mandatory for the scrapie isoform (PrPSC) to exert its toxicity, whether PrPSC replication in neurons potentiates their sensitivity to inflammatory cytokines is unclear. Objectives: Our goal was 1) to assess the impact of prion infection in neuronal cells on TNFα-mediated toxicity and 2) to relate these effects to the normal function of PrPC. Methods: Our study is based on RT-PCR, western blot and immunofluorescence experiments. We take advantage of the neuroectodermal 1C11 cell line endowed with the capacity to differentiate into bioaminergic neuronal cells. 1C11 cells combine functional expression of endogenous PrPC and the ability to chronically replicate several prion strains. Experiments were also carried out on primary cerebellar granule neurons obtained from FVB WT or PrP-null mice and FVB infected mice with 22L prions. Results: In 1C11 precursors and their neuronal progenies, infection with the Fukuoka or 22L strains renders cells more vulnerable to exogenous TNFα. This higher cell sensitivity to TNFα relates to an increased expression of the death receptor TNFR1 at the surface of infected cells, itself resulting from both an upregulation of TNFR1 transcripts and an inhibition of metalloproteinase-dependent TNFR1 shedding. The raise in TNFR1 was also monitored in brains of 22L infected mice. Finally, we provide evidence that PrPC depletion promotes a deregulation in TNFR1 that compares that observed within an infectious context. Discussion: We substantiate an increased vulnerability of infected neuronal cells to inflammatory cytokines, that reflects a loss of PrPC function on TNF-R1 regulation. We propose that the altered cell response to TNFα-mediated toxicity contributes to exacerbate prion-induced pathogenesis.
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