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

Acta Neuropathol Commun. 2023 Aug 18;11(1):134. doi: 10.1186/s40478-023-01635-5.

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 α/β 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. Molecular alteration of reactive microglia also occurred with diminished expression of genes 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.

Keywords: Microglia; Neurodegeneration; Neuroimmune; Neuroinflammation; Traumatic brain injury; Type I interferon.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies
  • Brain
  • Brain Injuries, Traumatic* / complications
  • Interferon Type I*
  • Male
  • Mice
  • Neuropathology

Substances

  • Interferon Type I
  • Antibodies