Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury
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 expe...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01635-5 |
| _version_ | 1797555820129419264 |
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| author | Brittany P. Todd Zili Luo Noah Gilkes Michael S. Chimenti Zeru Peterson Madison R. Mix John T. Harty Thomas Nickl-Jockschat Polly J. Ferguson Alexander G. Bassuk Elizabeth A. Newell |
| author_facet | Brittany P. Todd Zili Luo Noah Gilkes Michael S. Chimenti Zeru Peterson Madison R. Mix John T. Harty Thomas Nickl-Jockschat Polly J. Ferguson Alexander G. Bassuk Elizabeth A. Newell |
| author_sort | Brittany P. Todd |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T16:53:04Z |
| format | Article |
| id | doaj.art-8c8d670c025e4719a03715fdbd6ee349 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-10T16:53:04Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-8c8d670c025e4719a03715fdbd6ee3492023-11-20T11:15:10ZengBMCActa Neuropathologica Communications2051-59602023-08-0111111610.1186/s40478-023-01635-5Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injuryBrittany P. Todd0Zili Luo1Noah Gilkes2Michael S. Chimenti3Zeru Peterson4Madison R. Mix5John T. Harty6Thomas Nickl-Jockschat7Polly J. Ferguson8Alexander G. Bassuk9Elizabeth A. Newell10Medical Scientist Training Program, University of IowaDepartment of Pediatrics, University of IowaDepartment of Pediatrics, University of IowaBioinformatics Division, Iowa Institute of Human Genetics, University of IowaDepartment of Neuroscience and Pharmacology, University of IowaMedical Scientist Training Program, University of IowaDepartment of Pathology and Interdisciplinary Graduate Program in Immunology, University of IowaDepartment of Neuroscience and Pharmacology, University of IowaDepartment of Pediatrics, University of IowaDepartment of Pediatrics, University of IowaDepartment of Pediatrics, University of IowaAbstract 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.https://doi.org/10.1186/s40478-023-01635-5Traumatic brain injuryType I interferonNeuroinflammationNeurodegenerationMicrogliaNeuroimmune |
| spellingShingle | Brittany P. Todd Zili Luo Noah Gilkes Michael S. Chimenti Zeru Peterson Madison R. Mix John T. Harty Thomas Nickl-Jockschat Polly J. Ferguson Alexander G. Bassuk Elizabeth A. Newell Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury Acta Neuropathologica Communications Traumatic brain injury Type I interferon Neuroinflammation Neurodegeneration Microglia Neuroimmune |
| title | Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury |
| title_full | Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury |
| title_fullStr | Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury |
| title_full_unstemmed | Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury |
| title_short | Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury |
| title_sort | selective neuroimmune modulation by type i interferon drives neuropathology and neurologic dysfunction following traumatic brain injury |
| topic | Traumatic brain injury Type I interferon Neuroinflammation Neurodegeneration Microglia Neuroimmune |
| url | https://doi.org/10.1186/s40478-023-01635-5 |
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