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Title: Preconditioning of microglia by α-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation.
Authors: Roodveldt, Cintia
Labrador-Garrido, Adahir
Gonzalez-Rey, Elena
Lachaud, Christian C
Guilliams, Tim
Fernandez-Montesinos, Rafael
Benitez-Rondan, Alicia
Robledo, Gema
Hmadcha, Abdelkrim
Delgado, Mario
Dobson, Christopher M
Pozo, David
metadata.dc.contributor.authoraffiliation: [Roodveldt,C; Labrador-Garrido,A; Lachaud,CC; Fernandez-Montesinos,R; Benitez-Rondan,A; Hmadcha A; Pozo,D] CABIMER, Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain. [Labrador-Garrido,A; Fernandez-Montesinos,R; Pozo,D] Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Seville, Spain. [Gonzalez-Rey,E; Robledo,G Delfgadno,M] Institute of Parasitology and Biomedicine ‘Lopez-Neyra’, CSIC, Granada, Spain. [Dobson,CM] Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
Keywords: Microglial cells;Cytokines;Toll-Like Receptors;Fluorescence microscopy;Phagocytosis;Chemokines;Fluorescence imaging;Secretion;Receptores Toll-Like;Citocinas;Microscopía Fluorescente;Fagocitosis
metadata.dc.subject.mesh: Medical Subject Headings::Organisms::Eukaryota::Animals
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Ureohydrolases::Arginase
Medical Subject Headings::Organisms::Bacteria::Gram-Positive Bacteria::Bacillales::Bacillaceae::Bacillus::Bacillus subtilis
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Apoptosis Regulatory Proteins::Caspases::Caspases, Effector::Caspase 3
Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Polarity
Medical Subject Headings::Anatomy::Cells::Cells, Cultured
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression
Medical Subject Headings::Phenomena and Processes::Immune System Phenomena::Immunity::Immunity, Innate
Medical Subject Headings::Check Tags::Male
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains::Mice, Inbred C57BL
Medical Subject Headings::Anatomy::Cells::Neuroglia::Microglia
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Oxidoreductases Acting on CH-NH2 Group Donors::Amino Acid Oxidoreductases::Nitric Oxide Synthase::Nitric Oxide Synthase Type II
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Glycopeptides::Peptidoglycan
Medical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleotides::Polynucleotides::Polyribonucleotides::Poly C::Poly I-C
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Pattern Recognition::Toll-Like Receptors
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins::Synucleins::alpha-Synuclein
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Quinolines::Aminoquinolines
Issue Date: 2013
Publisher: Public Library of Science
Citation: Roodveldt C, Labrador-Garrido A, Gonzalez-Rey E, Lachaud CC, Guilliams T, Fernandez-Montesinos R, et al. Preconditioning of microglia by α-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation. PLoS ONE; 8(11):e79160
Abstract: 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.
Description: Journal Article; Research Support, Non-U.S. Gov't;
metadata.dc.identifier.doi: 10.1371/journal.pone.0079160
ISSN: 1932-6203 (Online)
Appears in Collections:01- Artículos - CABIMER. Centro Andaluz de Biología Molecular

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