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.

Expression and functions of cellular prion proteins in immunocytes

“…Expression differences have been detected in several unknown cell types, and its concrete functions require further exploration. Importantly, certain proteins, such as TLRs, respond differently to PrP C and PrP Sc . How these differences are recognized and mediated is quite thought‐provoking and could provide valuable targets for pharmacological agents against prion diseases.…”

“…Importantly, certain proteins, such as TLRs, respond differently to PrP C and PrP Sc . 36,45 How these differences are recognized and mediated is quite thought-provoking and could provide valuable targets for pharmacological agents against prion diseases.…”

Neuroinflammation in the central nervous system: Symphony of glial cells

“…TLR3 locates in the endosome and specifically recognizes double stranded RNAs, which indicates its role in the defense against viruses. TLR4 is mainly triggered by lipopolysaccharide (LPS) from gram-negative bacteria and endogenous DAMPs, such as high-mobility group box-1 (HMGB-1), heat shock proteins (HSPs) released from injured tissues (Laird et al, 2014;Rosenberger et al, 2015) or accumulated mis-folded proteins, such as α-synuclein or prion (Fellner et al, 2013;Kang et al, 2016). Microglia in human and rodents express nearly all types of TLRs (TLR1-13), particularly TLR4 and TLR2 (Konat et al, 2006;Lehnardt, 2010).…”

Identification of anti-prion drugs and targets using toxicity-based assays

“…To identify therapeutic agents that block prion neurotoxicity, it would be desirable to employ neuron-based assay systems that reproduce these toxic effects in vitro. However, there has been relatively little published literature on prion infection of cultured primary neurons, and it has not been clear how well these cells propagate prions or how they respond to the infectious process [34][35][36][37]. Our laboratory has recently developed a neuronal culture system that reproduces one of the earliest and potentially most critical steps in prion neurotoxicity: synaptic damage.…”