Pinteaux-Jones, F.; (2007) A study of microglial metabotropic glutamate receptor modulation of inflammation. Doctoral thesis , University of London.

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Abstract

Microglia are the immune cell of the central nervous system and become reactive in response to infection or trauma. In Multiple Sclerosis (MS) microglia show early reactivity which may contribute to subsequent neurotoxicity. Glutamate has been implicated in the neurodegeneration in MS. Microglia express subtypes of metabotropic glutamate receptors (mGluRs), the activation of which can lead to microglial evoked neurotoxicity (group II) or neuroprotection (group III). This suggests that release of glutamate from neurones or glial cells may activate microglia via these receptors. Increased microglial reactivity during disease is possibly due to an imbalance of mGluR expression with neurotoxic group II increased above neuroprotective group III mGluRs. Microglial expression of mGluR subtypes was therefore investigated on activated compared with untreated cells. It was found that microglia exposed to myelin expressed increased levels of group II and mGluRl and 8 subtypes compared with control cells. MS is characterised by lesions in the CNS due to localised myelin breakdown. This research investigated the effects of microglial exposure to myelin and demonstrated that myelin induced microglial activation, upregulation of iNOS expression, and increased TNFa and nitrite release. Conditioned medium from these cells was toxic to neurones in culture. Microglia phagocytose myelin in vitro leading to cytokine release and increased affinity for oligodendrocytes, inducing their death by cell contact through TNF receptors. This study examined whether microglial phagocytosis could be modulated by stimulation of mGluRs and demonstrated that blocking group II or stimulation of group I or III mGluRs significantly reduced phagocytic activity. Since myelin induced toxicity was also reduced by blocking microglial group II or stimulating group III mGluRs, these results suggest that modulation of microglial mGluRs may be of therapeutic benefit in MS.

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