Role of IFNGR1 in reactive astrocyte activation

This project aims to determine how inflammation in tissues outside the brain can influence the progression of neuronal damage within the brain. Astrocytes are important types of cells in the brain known as glial cells. Normally these cells provide factors that help support the health of the neurons within the brain. However, under certain circumstances these cells can also undergo reactive astrocytosis following brain injury and during neurodegeneration, and this can lead to neuronal death. Little is known of the molecular mechanisms that underpin these distinct astrocyte activities, but a key study shows how certain signals from microglia (specialized phagocytes in the brain) can trigger neurotoxic astrocyte activity. Prions cause fatal neurodegenerative diseases that affect animals and humans to which there are no cures. Our recent data show that interferon-gamma receptor 1 (IFNGR1) is highly and specifically expressed by the reactive astrocytes that are induced in the brain in response to the neurodegeneration that occurs during prion disease. We also show production of the cytokine interferon-gamma, due to the immune response to infection with an intestinal worm parasite in the intestine, can enhance the neurotoxic profile of these IFNGR1+ astrocytes. As a consequence, the neuronal damage caused by the prion infection in the brain is accelerated. Other studies have shown that IFNGR1 is also expressed in astrocytes in the aging human brain and in patients with Parkinson's disease and Alzheimer's disease. This suggests that IFNGR1 signalling may be an important mediator of neurotoxic astrocyte activation in many pathological brain disorders. However, little is known of the precise function of IFNGR1+ astrocytes and the effects they have on the neurons in the brain. This proposal therefore aims to address the important knowledge gaps in our understanding of the role of IFNGR1 signalling in astrocyte activation. Specifically, our experiments are designed to test the hypothesis that IFN-gamma-IFNGR1 signalling in astrocytes is an important trigger of neurotoxic reactive astrocyte activation, and this leads to accelerated neuronal damage.

The main aims and hypotheses of this project are to determine:
1. whether microglia-derived factors are required for the induction and maintenance of IFNGR1+ reactive astrocytes in their differentiated state
2. the function of INFGR1+ reactive astrocytes
3. whether and how astrocyte-specific IFNGR1-stimulation accelerates neuronal damage in the brain

Since IFNGR1+ reactive astrocytes have been identified in a range of pathological CNS disorders, a thorough understanding of their phenotype will have widespread application. Since treatments that modulate the neurotoxic activities of astrocytes can help prevent neuronal damage, data from this study may help identify novel treatments to counteract the adverse effects of systemic IFN-gamma responses (such as those induced in response to systemic/intestinal pathogen infections) on the progression of some neurodegenerative disorders. These data may also aid development of novel methods to help counteract the adverse effects of aging on the brain.

Astrocytes are important glial cells in the brain that provide homeostatic support to neurons in the steady state, but can undergo reactive astrocytosis after brain injury and during neurodegeneration. Little is known of the mechanisms underpinning these properties, but microglial-derived TNF, IL-1a and complement C1q can induce neurotoxic astrocytes. Our data show that interferon-gamma receptor 1 (IFNGR1) is highly expressed by reactive astrocytes during neurodegeneration. Furthermore, a systemic Th1-polarized IFN-gamma-mediated inflammatory response induced by an intestinal pathogen co-infection enhances the neurotoxic profile of IFNGR1+ astrocytes, accelerating neurodegeneration. IFNGR1+ astrocytes also occur in the aging human brain and in patients with other neurodegenerative diseases, suggesting that IFNGR1 signalling is an important mediator of neurotoxic astrocyte activation. Little is known of the in vivo phenotype of IFNGR1+ astrocytes. Our previous data show that neuropathology during CNS prion disease is unaffected in TNFa-/- and C1q-/- mice indicating that other microglial-derived stimuli induce IFNGR1+ reactive astrocytes. This study will address these important knowledge gaps and test the hypothesis that IFNGR1 signalling is a key mediator of neurotoxic reactive astrocyte activation.

The main aims are to determine: 1, the microglia-derived factors that are required for the induction and maintenance of IFNGR1+ reactive astrocytes; 2, the phenotype of INFGR1+ reactive astrocytes; 3, whether astrocyte-specific IFNGR1-signalling accelerates neurodegeneration in vivo.

Data from this study will have widespread application. This study may help identify novel treatments to counteract the adverse effects of systemic IFN-gamma responses (eg: during systemic/intestinal pathogen infections) on the progression of some neurodegenerative diseases. These data may also aid development of new methods to help counteract the adverse effects of aging on the brain.