Modulation of the innate immune response by NMDA receptors has neuropathological consequences.
The aim of this study was to determine whether glutamate receptors modulate the innate immune response in the brain of C3H/HeN and C3H/HeJ mice; the latter bear a loss of function in the toll-like receptor (TLR) 4 gene. Mice received an intrastriatal (IS) infusion of lipopolysaccharide (LPS), the exogenous ligand for TLR4, and were killed at several times thereafter. This treatment activated the transcription of a wide variety of genes involved in the control of the innate immune response. MK-801, an antagonist of NMDA glutamate receptor subtype, exacerbated the effects of the endotoxin in the brain of C3H/HeN mice but not in TLR4-deficient animals. The ipsilateral side of C3H/HeN mice exhibited stronger hybridization signals for the mRNA encoding TLR2, CD14, tumor necrosis factor-alpha, and inhibitory factor-kappaBalpha at various times after the treatment combining MK-801 and LPS. This robust inflammatory response in the brain of C3H/HeN mice was not associated with any convincing signs of neurodegeneration or demyelination that was verified via numerous approaches and at time up to 2 weeks after injection. However, animals that received long-term IS infusion of LPS, together with MK-801, exhibited a significant increase in demyelination levels within the ipsilateral side. Our results demonstrate that binding of glutamate to its cognate NMDA receptor modulates LPS-induced innate immune reaction in a TLR4-dependent manner. This acute response may be crucial to eliminate bacterial cell wall components and minimizing tissue injury. However, sustained deregulation of proinflammatory signaling involving NMDA receptors leads to demyelination and is likely to be a mechanism participating in such pathological conditions.
Glezer
Isaias
I
Laboratory of Molecular Endocrinology, Centre Hospitalier Université Laval Research Center, and Department of Anatomy and Physiology, Laval University, Québec, Canada G1V 4G2.
Zekki
Hakima
H
Scavone
Cristoforo
C
Rivest
Serge
S
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004333:Drug Administration Routes; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D004731:Endotoxins / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D017403:In Situ Hybridization; D018950:Lipopolysaccharide Receptors / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000187:drug effects / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013995:Time; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D016291:Dizocilpine Maleate; D004731:Endotoxins; D018691:Excitatory Amino Acid Antagonists; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors