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Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Plastira, I; Bernhart, E; Goeritzer, M; DeVaney, T; Reicher, H; Hammer, A; Lohberger, B; Wintersperger, A; Zucol, B; Graier, WF; Kratky, D; Malle, E; Sattler, W.
Lysophosphatidic acid via LPA-receptor 5/protein kinase D-dependent pathways induces a motile and pro-inflammatory microglial phenotype.
J Neuroinflammation. 2017; 14(1):253-253 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG


Autor/innen der Med Uni Graz:
Bernhart Eva Maria
Devaney Trevor
Göritzer Madeleine
Graier Wolfgang
Hammer Astrid
Kratky Dagmar
Lohberger Birgit
Malle Ernst
Plastira Ioanna
Reicher Helga
Sattler Wolfgang
Wintersperger Andrea

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Plum Analytics:
Number of Figures: 16
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Extracellular lysophosphatidic acid (LPA) species transmit signals via six different G protein-coupled receptors (LPAR1-6) and are indispensible for brain development and function of the nervous system. However, under neuroinflammatory conditions or brain damage, LPA levels increase, thereby inducing signaling cascades that counteract brain function. We describe a critical role for 1-oleyl-2-hydroxy-sn-glycero-3-phosphate (termed "LPA" throughout our study) in mediating a motile and pro-inflammatory microglial phenotype via LPAR5 that couples to protein kinase D (PKD)-mediated pathways. Using the xCELLigence system and time-lapse microscopy, we investigated the migrational response of microglial cells. Different M1 and M2 markers were analyzed by confocal microscopy, flow cytometry, and immunoblotting. Using qPCR and ELISA, we studied the expression of migratory genes and quantitated the secretion of pro-inflammatory cytokines and chemokines, respectively. Different transcription factors that promote the regulation of pro-inflammatory genes were analyzed by western blot. Reactive oxygen species (ROS) and nitric oxide (NO) production, phagocytosis, and microglial cytotoxicity were determined using commercially available assay kits. LPA induces MAPK family and AKT activation and pro-inflammatory transcription factors' phosphorylation (NF-κB, c-Jun, STAT1, and STAT3) that were inhibited by both LPAR5 and PKD family antagonists. LPA increases migratory capacity, induces secretion of pro-inflammatory cytokines and chemokines and expression of M1 markers, enhances production of ROS and NO by microglia, and augments cytotoxicity of microglial cell-conditioned medium towards neurons. The PKD family inhibitor blunted all of these effects. We propose that interference with this signaling axis could aid in the development of new therapeutic approaches to control neuroinflammation under conditions of overshooting LPA production. In the present study, we show that inflammatory LPA levels increased the migratory response of microglia and promoted a pro-inflammatory phenotype via the LPAR5/PKD axis. Interference with this signaling axis reduced microglial migration, blunted microglial cytotoxicity, and abrogated the expression and secretion of pro-inflammatory mediators.
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Animals -
Animals, Newborn -
Carboxylic Acids - pharmacology
Cell Movement - drug effects
Cells, Cultured -
Cerebral Cortex - cytology
Cytokines - genetics
Cytokines - metabolism
Enzyme Inhibitors - pharmacology
Lysophospholipids - pharmacology
Mice -
Mice, Inbred C57BL -
Microglia - drug effects
Neurons - drug effects
Phosphorylation -
Protein Kinase C - genetics
Protein Kinase C - metabolism
Pyrimidines - pharmacology
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Reactive Oxygen Species - metabolism
Receptors, Lysophosphatidic Acid - antagonists & inhibitors
Receptors, Lysophosphatidic Acid - metabolism
Signal Transduction - drug effects

Find related publications in this database (Keywords)
Bioactive lipids
Signal transduction
Pro-inflammatory mediators
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