title: Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia.
abstract: Alpha-synucleinopathies (ASP) are neurodegenerative disorders, characterized by accumulation of misfolded α-synuclein, selective neuronal loss, and extensive gliosis. It is accepted that microgliosis and astrogliosis contribute to the disease progression in ASP. Toll-like receptors (TLRs) are expressed on cells of the innate immune system, including glia, and TLR4 dysregulation may play a role in ASP pathogenesis. In this study we aimed to define the involvement of TLR4 in microglial and astroglial activation induced by different forms of α-synuclein (full length soluble, fibrillized, and C-terminally truncated). Purified primary wild type (TLR4(+/+)) and TLR4 deficient (TLR4(-/-)) murine microglial and astroglial cell cultures were treated with recombinant α-synuclein and phagocytic activity, NFκB nuclear translocation, cytokine release, and reactive oxygen species (ROS) production were measured. We show that TLR4 mediates α-synuclein-induced microglial phagocytic activity, pro-inflammatory cytokine release, and ROS production. TLR4(-/-) astroglia present a suppressed pro-inflammatory response and decreased ROS production triggered by α-synuclein treatment. However, the uptake of α-synuclein by primary astroglia is not dependent on TLR4 expression. Our results indicate the C-terminally truncated form as the most potent inductor of TLR4-dependent glial activation. The current findings suggest that TLR4 plays a modulatory role on glial pro-inflammatory responses and ROS production triggered by α-synuclein. In contrast to microglia, the uptake of alpha-synuclein by astroglia is not dependent on TLR4. Our data provide novel insights into the mechanisms of α-synuclein-induced microglial and astroglial activation which may have an impact on understanding the pathogenesis of ASP.
authors.affiliation: Division of Neurobiology, Innsbruck Medical University, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Fellner
authors.forename: Regina
authors.initials: R
authors.lastname: Irschick
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schanda
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.forename: Lars
authors.initials: L
authors.lastname: Klimaschewski
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051844:alpha-Synuclein / Q000494:pharmacology*
chemical_list: D054360:Chemokine CXCL1; D015850:Interleukin-6; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D051844:alpha-Synuclein