Lysophosphatidic acid receptor type 2 activation contributes to secondary damage after spinal cord injury in mice |
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| Affiliation: | 1. Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Bellaterra, Catalonia 08193, Spain;2. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA;1. Molecular Neurobiology Laboratory, Neurology, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany;2. Institute of Microsystems Technology, Technical University of Hamburg-Harburg, Eißendorfer Straße 42, 21073 Hamburg, Germany;3. BG Trauma Hospital Hamburg, Department of Trauma Surgery, Orthopaedics and Sports Traumatology, Bergedorfer Straße 10, 21033 Hamburg, Germany;1. Department of Biochemistry and Molecular Biology, Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;2. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA;3. Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan;4. Vascular Biology Program, Boston Children''s Hospital, Boston, MA 20115, USA;5. Department of Surgery, Harvard Medical School, Boston, MA 20115, USA;6. Department of Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan;7. PharmaCo-Cell Company Ltd., Nagasaki 852-0862, Japan;1. Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA;2. Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA;1. Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China;2. Department of Anesthesiology, The First People’s Hospital of Lianyungang City, Lianyungang, China |
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| Abstract: | Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions by signaling through six known G-protein-coupled receptors (LPA1-LPA6). In the central nervous system (CNS), LPA mediates a wide range of effects, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and contributions to pain, schizophrenia and hydrocephalus. We recently reported that LPA-LPA1 signaling mediates functional deficits and myelin loss after spinal cord injury (SCI). Here, we provide clear evidence on the deleterious contribution of another LPA receptor, LPA2, to myelin loss after SCI. We found that LPA2 is constitutively expressed in the spinal cord parenchyma and its transcripts were up-regulated after contusion injury, in part, by microglial cells. We also found that the demyelinating lesion triggered by intraspinal injection of LPA into the undamaged spinal cord was markedly reduced in the lack of LPA2. Similarly, LPA2 deficient mice showed enhanced motor skills and myelin sparing after SCI. To gain insights into the detrimental actions of LPA2 in spinal cord we performed cell culture studies. These experiments revealed that, similar to LPA1, activation of microglia LPA2 led to oligodendrocyte cell death. Moreover, we also found that the cytotoxic effects underlaying microglial LPA-LPA2 axis were mediated by the release of purines by microglia and the activation of P2X7 receptor on oligodendrocytes. Overall, this study provides new mechanistic insights into how LPA contributes to SCI physiopathology, and suggest that targeting LPA2 could be a novel therapeutic approach for the treatment of acute SCI. |
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| Keywords: | Demyelination Lysophosphatidic acid Inflammation Neurodegeneration Microglia Spinal cord injury |
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