Role of IFNGR1 in reactive astrocyte activation

Award Number
BB/V006444/1
Status / Stage
Active
Dates
4 January 2021 -
3 October 2024
Duration (calculated)
03 years 08 months
Funder(s)
BBSRC (UKRI)
Funding Amount
£560,720.00
Funder/Grant study page
BBSRC UKRI
Contracted Centre
University of Edinburgh
Principal Investigator
Professor Neil Mabbott
PI Contact
neil.mabbott@roslin.ed.ac.uk
PI ORCID
0000-0001-7395-1796
WHO Catergories
Understanding Underlying Disease
Disease Type
Dementia (Unspecified)

CPEC Review Info
Reference ID734
ResearcherReside Team
Published07/07/2023

Data

Award NumberBB/V006444/1
Status / StageActive
Start Date20210104
End Date20241003
Duration (calculated) 03 years 08 months
Funder/Grant study pageBBSRC UKRI
Contracted CentreUniversity of Edinburgh
Funding Amount£560,720.00

Abstract

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.

Aims

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.