Microglia are increasingly implicated in the signalling cascades leading to neuronal death in a large number of neuroinflammatory diseases, including Alzheimer’s disease, multiple sclerosis, Parkinson’s disease and also in acute conditions such as those following stroke. Using cell based systems, we are investigating signalling cascades which occur in microglia following their exposure to substances implicated in their activation in particular neurodegenerative diseases. Our aim is to dissect out the pathways of neuronal death which result from microglial activation.
We have discovered that microglia express functional metabotropic glutamate (mGlu) receptors. Whilst these receptors have received considerable attention for their roles in signalling cascades in neurones, their role in microglia is unclear. We have determined that activation of the different groups of mGluRs on microglia has considerable ramifications for the subsequent microglial phenotype (Dr Deana Taylor). Thus, activation of mGlu2 (group II) results in the transformation of microglia from a non-toxic to a neurotoxic phenotype. This is induced by release of the inflammatory cytokine, tumour necrosis alpha (TNFα) and the shedding of microglia Fas ligand (FasL). When both of these occur, microglia induce neuronal death mediated by TNFR1 and Fas receptor stimulation, leading to the activation of caspase 3 and subsequent neuronal apoptosis. Conversely we have also found that the activation of group III mGlu receptors (which includes mGlu4, 6 and 8) leads to a ne protective microglial phenotype when microglia are exposed to activators which would otherwise lead to their neurotoxic transformation. These results have significant ramifications for our understanding of microglial activation in neurodegenerative diseases because any cellular stress in the brain leads to a reversal of the uptake of glutamate from the intracellular space, leading to an elevation of extracellular glutamate which could in turn lead to the activation and recruitment of microglia via stimulation of their mGlu receptors. We are also investigating how different stimuli may alter the expression and dominance of activation of one type of mGlu receptor on microglia versus another since this could determine the switching of microglia from a neurotoxic to a neuroprotective phenotype (Ms Fleur Jones).