Cellular and molecular mechanisms of macrophage-mediated neuroprotection

Secondary cell death plays an important role in the pathophysiology of traumatic brain injury, spinal cord injury and stroke. Neuroinflammation was thought to contribute to secondary cell death, but clinical trials have shown that anti-inflammatory drugs can in fact be harmful. This suggests that inflammation can be neuroprotective, but the underlying mechanisms are not understood. Our preliminary results using an accessible larval zebrafish model of brain injury show that secondary cell death is strongly increased in a zebrafish mutant that lacks macrophages.

We will investigate the mechanisms underlying the neuroprotective effect of macrophages. We aim to determine the contribution of debris phagocytosis and identify macrophage-derived neuroprotective molecules. We will combine confocal live imaging of cell death indicators with pharmacological and genetic inhibition of phagocytosis to investigate the contribution of rapid debris clearance to macrophage-mediated neuroprotection. We will also use in situ hybridisation screening and RNA-seq expression profiling of macrophages that have been purified by fluorescence-activated cell sorting to identify macrophage-derived neuroprotective molecules.

This work will provide insight into the cellular and molecular mechanisms of inflammatory neuroprotection and will identify targets for manipulation of the mammalian immune system aimed at reducing secondary cell death after injury to the central nervous system.