Macrophage participation in the hepatic response to acute CNS injury.

We are committed to improving public engagement in science and we will ensure that work carried under under this proposal will be communicated to those outside the scientific community. We have established a web site to disseminate details of our research (www.pharm.ox.ac.uk). If the application is successful, the lay summary will be placed on the web sites, which will be updated as the milestones are reached. We have given, and will be giving, public lectures on the theme of this proposal, we are also involved in a local Schools science programme, and we will release items about our work to the Oxford University Press Office after they have been published in peer-reviewed journals.

Local tissue inflammation is also accompanied by regulatory responses in organs away from the primary injury site, which is known as the systemic Acute Phase Response (APR). Injury to the brain or spinal cord also generates an APR. We have discovered, using GeneChip analysis, convention molecular biology, and immuno methods, that the APR after brain injury results in the activation of cells in the liver to produce molecules, known as chemokines, which increase the number of immune cells circulating in the blood. These increased numbers of immune cells migrate not only into the brain where they damage nerve cells, but also into the liver where they cause injury. There is now a need to understand the signalling events that regulate this system and to learn more about the cell populations that are responsible for steering the hepatic APR to CNS injury. Under this proposal, we will test our hypothesis that resident microglia in the brain and Kupffer cells in the liver are the primary mediators of the hepatic APR. We will employ three strategies to target macrophage function in the periphery and in the CNS: (1) we will use newly developed CD11b-HSVTK transgenic mice to achieve microglial paralysis, (2) we will employ peripheral injections of clodronate filled liposomes to selectively deplete Kupffer cells in the liver, and (3) we will suppress Kupffer cell function by the use of a replication deficient adenovirus expressing the IkBa super-repressor gene, which will block NFkB activity. In this way, we expect to discover that elimination or suppression of microglial function in the brain will prevent the initiation of an acute phase response to CNS injury and that the Kupffer cell inactivation will lead to a decrease in the production of hepatic chemokines and a decrease in the mobilisation and recruitment of neutrophils to the liver and to the brain. Furthermore, it is still unclear how macrophage populations contribute to the febrile response. We will use telemetry to discover how microglial paralysis or Kupffer cell depletion contributes to the febrile response initiated by CNS injury. Understanding the cellular and molecular pathways that control the liver-brain axis in the inflammatory response to brain injury will open up therapeutic avenues that can be exploited for clinical treatments to reduce damage to the brain and spinal cord, a significant cause of human morbidity.