The role of the innate immune system in neural injury

© 2011 Dr. Catherine DownesThe response to the hypoxia and ischemia that occurs in the CNS during and following a stroke involves many inflammatory mediators and cell types. The spread and subsequent control of inflammation can dictate the extent of injury caused by the stroke, therefore understanding the development and regulation of inflammation following stroke could lead to better therapeutic options. The Toll-like receptors have traditionally been known as pathogen detectors. Their ligand range is now extending to include many endogenous molecules that are released under stressful or lethal cellular conditions. Their expression in the brain suggests that they may be involved in the post-stroke spread of inflammation. Toll-like receptors signal through adaptor proteins. Mice deficient in a key adaptor protein myeloid differentiation factor-88 (MyD88) were used to assess the role of the innate immune system in the response to cerebral inflammation. The role of MyD88-dependent signalling in response to CNS hypoxia/ischemia was first assessed through the response of primary cultured glia and neurons to oxygen and glucose deprivation (OGD). Cultured alone there was no difference in the response to OGD between the MyD88-/- and WT cells. The addition of glia to the neuronal cultures significantly increased the ability of the MyD88-/- neurons only to survive. Suggesting that MyD88-independent signalling, when driven by glia can be neuroprotective. In response to middle cerebral artery occlusion (MCAO) an in vivo model of stroke the MyD88-/- mice displayed a significantly larger infarct volume than the WT animals. Investigations using bone marrow chimera mice revealed that the contribution of MyD88-dependnet signalling to the development of infarct volume was primarily from cells of haematopoietic origin. MyD88-dependent signalling in the haematopoietic cells was demonstrated to be essential for their infiltration into the neuropil following MCAO. MyD88-dependent signalling was also found to be essential for the development of ischemic tolerance. Ischemic preconditioning twenty-four hours prior to OGD only afforded protection to WT neurons; furthermore, negative regulation of kinases was found to contribute to the lack of tolerance in the MyD88-/- neurons. This work has characterised MyD88-dependent signalling in response to ischemic and hypoxic stress in the CNS. MyD88-dependent signalling was found to be important for the infiltration of cells following MCAO and the development of ischemic tolerance in neurons. A foundation for further research into the Toll-like receptors as potential drug targets in the response to ischemia has been established