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Glia. 2016 Jun;64(6):937-51. doi: 10.1002/glia.22973. Epub 2016 Feb 16.

Toll-like receptor-mediated immune response inhibits prion propagation.

Author information

1
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
2
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
3
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
4
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
5
Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
6
Department of Agricultural, Food, and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada.

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.

KEYWORDS:

cytokines; glial cells; immune competent cells; innate immunity; prion defense

PMID:
26880394
DOI:
10.1002/glia.22973
[Indexed for MEDLINE]

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