Role of adaptor protein MyD88 in TLR-mediated preconditioning and neuroprotection after acute excitotoxicity

Brain, Behavior, and Immunity
Antoine LarochelleSerge Rivest

Abstract

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 hematopoieti...Continue Reading

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Citations

Dec 1, 2015·Journal of Neuroimmunology·Mansoureh EslamiMahmoudreza Hadjighassem
Jan 10, 2020·Neurological Research·Mansoureh EslamiMohammad Sayyah
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Nov 9, 2017·International Journal of Molecular Medicine·Meiling JinWeizhen Zhang
May 8, 2018·Frontiers in Pharmacology·Yangyang YuWeizhen Zhang
Dec 20, 2018·Physiological Reviews·Meng XuHongliang Li
Jul 3, 2021·International Journal of Molecular Sciences·Rezan Ashayeri AhmadabadMaryam Khaleghi Ghadiri
Aug 19, 2021·Metabolic Brain Disease·Tiffany J Petrisko, Gregory W Konat

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