title: Toll-like receptor-mediated immune response inhibits prion propagation.
abstract: Prion diseases are progressive neurodegenerative disorders affecting humans and various mammals. The prominent neuropathological change in prion diseases is neuroinflammation characterized by activation of neuroglia surrounding prion deposition. The cause and effect of this cellular response, however, is unclear. We investigated innate immune defenses against prion infection using primary mixed neuronal and glial cultures. Conditional prion propagation occurred in glial cultures depending on their immune status. Preconditioning of the cells with the toll-like receptor (TLR) ligand, lipopolysaccharide, resulted in a reduction in prion propagation, whereas suppression of the immune responses with the synthetic glucocorticoid, dexamethasone, increased prion propagation. In response to recombinant prion fibrils, glial cells up-regulated TLRs (TLR1 and TLR2) expression and secreted cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6, granulocyte-macrophage colony-stimulating factor, and interferon-β). Preconditioning of neuronal and glial cultures with recombinant prion fibrils inhibited prion replication and altered microglial and astrocytic populations. Our results provide evidence that, in early stages of prion infection, glial cells respond to prion infection through TLR-mediated innate immunity.
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sang-Gyun
authors.initials: SG
authors.lastname: Kang
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Chiye
authors.initials: C
authors.lastname: Kim
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Cortez
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: María
authors.initials: M
authors.lastname: Carmen Garza
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.|Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Holger
authors.initials: H
authors.lastname: Wille
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.|Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.|Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Sim
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.|Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.|Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.|Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Debbie
authors.initials: D
authors.lastname: McKenzie
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.|Department of Agricultural, Food, and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Judd
authors.initials: J
authors.lastname: Aiken
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism*; D011328:Prions / Q000276:immunology / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D011328:Prions; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: cytokines; glial cells; immune competent cells; innate immunity; prion defense