System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes.
Elevated levels of extracellular glutamate cause excitotoxic oligodendrocyte cell death and contribute to progressive oligodendrocyte loss and demyelination in white matter disorders such as multiple sclerosis and periventricular leukomalacia. However, the mechanism by which glutamate homeostasis is altered in such conditions remains elusive. We show here that microglial cells, in their activated state, compromise glutamate homeostasis in cultured oligodendrocytes. Both activated and resting microglial cells release glutamate by the cystine-glutamate antiporter system xc-. In addition, activated microglial cells act to block glutamate transporters in oligodendrocytes, leading to a net increase in extracellular glutamate and subsequent oligodendrocyte death. The blocking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors or the system xc- antiporter prevented the oligodendrocyte injury produced by exposure to LPS-activated microglial cells in mixed glial cultures. In a whole-mount rat optic nerve, LPS exposure produced wide-spread oligodendrocyte injury that was prevented by AMPA/kainate receptor block and greatly reduced by a system xc- antiporter block. The cell death was typified by swelling and disruption of mitochondria, a feature that was not found in closely associated axonal mitochondria. Our results reveal a novel mechanism by which reactive microglia can contribute to altering glutamate homeostasis and to the pathogenesis of white matter disorders.
Domercq
María
M
Departamento de Neurociencias, Universidad del País Vasco, Leioa, Vizcaya, Spain.
Sánchez-Gómez
María Victoria
MV
Sherwin
Catherine
C
Etxebarria
Estibaliz
E
Fern
Robert
R
Matute
Carlos
C
D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003553:Cystine / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D006706:Homeostasis / Q000502:physiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D017628:Microglia / Q000378:metabolism* / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000633:toxicity
D027322:Amino Acid Transport System X-AG; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D003553:Cystine