Suchergebnisse

In recent years, it has become accepted that α-synuclein (αSyn) 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) αSyn 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 αSyn by augmenting IL-6, MCP-1/CCL2 or IP-10/CXCL10 secretion levels. Furthermore, we report a skewing of αSyn-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 αSyn-primed microglia after stimulation with these particular TLR agonists. Overall, we report a remarkable impact of non-aggregated αSyn pre-sensitization of microglia on TLR-mediated immunity, a phenomenon that could contribute to triggering the onset of sporadic α-synuclein-related neuropathologies. Figures 123 Citation: Roodveldt C, Labrador-Garrido A, Gonzalez-Rey E, Lachaud CC, Guilliams T, et al. (2013) Preconditioning of Microglia by α-Synuclein Strongly Affects the Response Induced by Toll-like Receptor (TLR) Stimulation. PLoS ONE 8(11): e79160. doi:10.1371/journal.pone.0079160 Editor: Nick Gay, University of Cambridge, United Kingdom Received: June 18, 2013; Accepted: September 18, 2013; Published: November 13, 2013 Copyright: © 2013 Roodveldt et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Financial support was provided by the Spanish Ministry of Science and Innovation-Carlos III Institute of Health according to the 'Plan Nacional de I+D+i 2008-2011' (PS09-2252 to DP, and CP10/00527 to CR) with co-funding by FEDER funds, the Andalusian Ministry of Health (PI-2010-0824 to DP), Economy, Science and Innovation (P10-CTS-6928 and P11-CTS-8161 to DP) and the PAIDI Program from the Andalusian Government (CTS-677 to DP). ALG holds a FPU Predoctoral Fellowship from the Spanish Ministry of Education (AP-2009/3816). The work of CMD is supported by the Wellcome Trust and the UK Medical and Biotechnological and Biological Sciences Research Council. TG is supported by Parkinson's UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. ; Peer reviewed