Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury

Todd, B. P.; Luo, Z.; Gilkes, N.; Chimenti, M. S.; Peterson, Z.; Mix, M.; Harty, J. T.; Nickl-Jockschat, T.; Ferguson, P. J.; Bassuk, A. G.; Newell, E. A.

doi:10.1101/2023.06.06.543774

bioRxiv · 10.1101/2023.06.06.543774

Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury

Todd, B. P.·Luo, Z.·Gilkes, N.·Chimenti, M. S.·Peterson, Z.·Mix, M.·Harty, J. T.·Nickl-Jockschat, T.·Ferguson, P. J.·Bassuk, A. G.·Newell, E. A.

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Abstract

Accumulating evidence suggests that type I interferon (IFN-I) signaling is a key contributor to immune cell-mediated neuropathology in neurodegenerative diseases. Recently, we demonstrated a robust upregulation of type I interferon-stimulated genes in microglia and astrocytes following experimental traumatic brain injury (TBI). The specific molecular and cellular mechanisms by which IFN-I signaling impacts the neuroimmune response and neuropathology following TBI remains unknown. Using the lateral fluid percussion injury model (FPI) in adult male mice, we demonstrated that IFN /{beta} receptor (IFNAR) deficiency resulted in selective and sustained blockade of type I interferon-stimulated genes following TBI as well as decreased microgliosis and monocyte infiltration. Phenotypic alteration of reactive microglia also occurred with diminished expression of molecules needed for MHC class I antigen processing and presentation following TBI. This was associated with decreased accumulation of cytotoxic T cells in the brain. The IFNAR-dependent modulation of the neuroimmune response was accompanied by protection from secondary neuronal death, white matter disruption, and neurobehavioral dysfunction. These data support further efforts to leverage the IFN-I pathway for novel, targeted therapy of TBI.

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Todd, B. P., Luo, Z., Gilkes, N., Chimenti, M. S., Peterson, Z., Mix, M., Harty, J. T., Nickl-Jockschat, T., Ferguson, P. J., Bassuk, A. G., Newell, E. A.. 2023-06-07. Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury. https://doi.org/10.1101/2023.06.06.543774

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