The inflammatory cytokine, interleukin-1 beta, mediates loss of astroglial glutamate transport and drives excitotoxic motor neuron injury in the spinal cord during acute viral encephalomyelitis.
Astrocytes remove glutamate from the synaptic cleft via specific transporters, and impaired glutamate reuptake may promote excitotoxic neuronal injury. In a model of viral encephalomyelitis caused by neuroadapted Sindbis virus (NSV), mice develop acute paralysis and spinal motor neuron degeneration inhibited by the AMPA receptor antagonist, NBQX. To investigate disrupted glutamate homeostasis in the spinal cord, expression of the main astroglial glutamate transporter, GLT-1, was examined. GLT-1 levels declined in the spinal cord during acute infection while GFAP expression was preserved. There was simultaneous production of inflammatory cytokines at this site, and susceptible animals treated with drugs that blocked IL-1beta release also limited paralysis and prevented the loss of GLT-1 expression. Conversely, infection of resistant mice that develop mild paralysis following NSV challenge showed higher baseline GLT-1 levels as well as lower production of IL-1beta and relatively preserved GLT-1 expression in the spinal cord compared to susceptible hosts. Finally, spinal cord GLT-1 expression was largely maintained following infection of IL-1beta-deficient animals. Together, these data show that IL-1beta inhibits astrocyte glutamate transport in the spinal cord during viral encephalomyelitis. They provide one of the strongest in vivo links between innate immune responses and the development of excitotoxicity demonstrated to date.
Prow
Natalie A
NA
Department of Microbiology and Parasitology, The University of Queensland, Brisbane, Australia.
Irani
David N
DN
D000208:Acute Disease; D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001693:Biological Transport, Active / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D018792:Encephalitis, Viral / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism*; D018836:Inflammation Mediators / Q000502:physiology; D053583:Interleukin-1beta / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D027322:Amino Acid Transport System X-AG; D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D018698:Glutamic Acid