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

Acta Neuropathologica Communications

Research

Michael S. Chimenti¹  Zeru Peterson²  Thomas Nickl-Jockschat³  John T. Harty⁴  Elizabeth A. Newell⁵  Zili Luo⁵  Polly J. Ferguson⁵  Noah Gilkes⁵  Alexander G. Bassuk⁵  Madison R. Mix⁶  Brittany P. Todd⁷ 

[1] Bioinformatics Division, Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA, USA;Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA;Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA;Department of Psychiatry, University of Iowa, Iowa City, IA, USA;Department of Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, USA;Department of Pediatrics, University of Iowa, 200 Hawkins Drive, 52242, Iowa City, IA, USA;Medical Scientist Training Program, University of Iowa, Iowa City, IA, USA;Department of Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, USA;Medical Scientist Training Program, University of Iowa, Iowa City, IA, USA;Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, USA;

关键词: Traumatic brain injury;    Type I interferon;    Neuroinflammation;    Neurodegeneration;    Microglia;    Neuroimmune;   

DOI  :  10.1186/s40478-023-01635-5

 received in 2023-06-08, accepted in 2023-08-05,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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