Role of adaptor protein MyD88 in TLR-mediated preconditioning and neuroprotection after acute excitotoxicity.
Excitotoxic cell death is a crucial mechanism through which neurodegeneration occurs in numerous pathologies of the central nervous system (CNS), such as Alzheimer's disease, stroke and spinal cord injury. Toll-like receptors (TLRs) are strongly expressed on microglial cells and are key regulators of the innate immune response to neuronal damage. However, it is still unclear whether their stimulation is protective or harmful in excitotoxic contexts. In this study, we demonstrate that systemic administration of lipopolysaccharide (LPS) or Pam3CSK4 24h prior to an intrastriatal injection of kainic acid (KA) significantly protected cortical neurons in the acute phase of injury. Protection could not be detected with the TLR3 ligand poly-IC. Histological analyses revealed that microglia of LPS and Pam3CSK4 pre-conditioned group were primed to react to injury and exhibited a stronger expression of Tnf and Tlr2 mRNA. We also found that mice deficient for MyD88, a critical adaptor protein for most TLR, were more vulnerable than WT mice to KA-induced excitotoxicity at early (12h and 24h) and late (10days) time points. Finally, bone-marrow chimeric mice revealed that MyD88 signaling in CNS resident cells, but not in cells of hematopoietic origin, mediates the protective effect. This study unravels the potential of TLR2 and TLR4 agonists to induce a protective state of preconditioning against KA-mediated excitotoxicity and further highlights the beneficial role of cerebral MyD88 signaling in this context.
Neuroscience Laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Blvd., Québec G1V 4G2, Canada.
Antoine
A
Larochelle
Neuroscience Laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Blvd., Québec G1V 4G2, Canada.
Marc-André
MA
Bellavance
Neuroscience Laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Blvd., Québec G1V 4G2, Canada. Electronic address: Serge.Rivest@crchudequebec.ulaval.ca.
Serge
S
Rivest
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D007608:Kainic Acid / Q000633:toxicity*; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D000066829:Neuroprotection / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
D055666:Lipopeptides; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; C508075:Pam(3)CSK(4) peptide; D051193:Toll-Like Receptors; D007608:Kainic Acid
Excitotoxicity; Microglia; MyD88; Neuroprotection; Preconditioning; Toll-like receptors