4.6 Article

Preconditioning of Microglia by α-Synuclein Strongly Affects the Response Induced by Toll-like Receptor (TLR) Stimulation

Journal

PLOS ONE
Volume 8, Issue 11, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0079160

Keywords

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Funding

  1. Spanish Ministry of Science and Innovation-Carlos III Institute of Health [PS09-2252, CP10/00527]
  2. FEDER funds
  3. Andalusian Ministry of Health, Economy, Science and Innovation [PI-2010-0824, P10-CTS-6928, P11-CTS-8161]
  4. PAIDI Program from the Andalusian Government [CTS-677]
  5. FPU Predoctoral Fellowship from the Spanish Ministry of Education [AP-2009/3816]
  6. Wellcome Trust
  7. UK Medical and Biotechnological and Biological Sciences Research Council
  8. Parkinson's UK
  9. Parkinson's UK [H-0903] Funding Source: researchfish

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In recent years, it has become accepted that alpha-synuclein (alpha Syn) has a key role in the microglia-mediated neuroinflammation, which accompanies the development of Parkinson's disease and other related disorders, such as Dementia with Lewy Bodies and Alzheimer's disease. Nevertheless, the cellular and molecular mechanisms underlying its pathological actions, especially in the sporadic forms of the diseases, are not completely understood. Intriguingly, several epidemiological and animal model studies have revealed a link between certain microbial infections and the onset or progression of sporadic forms of these neurodegenerative disorders. In this work, we have characterized the effect of toll-like receptor (TLR) stimulation on primary murine microglial cultures and analysed the impact of priming cells with extracellular wild-type (Wt) alpha Syn on the subsequent TLR stimulation of cells with a set of TLR ligands. By assaying key interleukins and chemokines we report that specific stimuli, in particular Pam3Csk4 (Pam3) and single-stranded RNA40 (ssRNA), can differentially affect the TLR2/1- and TLR7-mediated responses of microglia when pre-conditioned with alpha Syn by augmenting IL-6, MCP-1/CCL2 or IP-10/CXCL10 secretion levels. Furthermore, we report a skewing of alpha Syn-primed microglia stimulated with ssRNA (TLR7) or Pam3 (TLR2/1) towards intermediate but at the same time differential, M1/M2 phenotypes. Finally, we show that the levels and intracellular location of activated caspase-3 protein change significantly in alpha Syn-primed microglia after stimulation with these particular TLR agonists. Overall, we report a remarkable impact of non-aggregated alpha Syn pre-sensitization of microglia on TLR-mediated immunity, a phenomenon that could contribute to triggering the onset of sporadic alpha-synuclein-related neuropathologies.

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