Traumatic brain injury induces long-lasting changes in immune and regenerative signaling

There are no existing treatments for the long-term degenerative effects of traumatic brain injury (TBI). This is due, in part, to our limited understanding of chronic TBI and uncertainty about which proposed mechanisms for long-term neurodegeneration are amenable to treatment with existing or novel...

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Bibliographic Details
Published in:PloS one 2019-04, Vol.14 (4), p.e0214741-e0214741
Main Authors: Boone, Deborah R, Weisz, Harris A, Willey, Hannah E, Torres, Karen E O, Falduto, Michael T, Sinha, Mala, Spratt, Heidi, Bolding, Ian J, Johnson, Kathea M, Parsley, Margaret A, DeWitt, Douglas S, Prough, Donald S, Hellmich, Helen L
Format: Article
Language:English
Subjects:
Acute-Phase Proteins - metabolism
Analysis
Anesthesiology
Animal cognition
Animals
Biochemistry
Biology and Life Sciences
Brain
Brain injuries
Brain Injuries, Traumatic - complications
Brain Injuries, Traumatic - immunology
Brain Injuries, Traumatic - metabolism
Care and treatment
Cell survival
Cellular signal transduction
Complement system
Complement System Proteins - metabolism
Computational Biology
Cortex (temporal)
Dementia
DNA microarrays
Drugs
Exercise
Gene expression
Gene Expression Profiling
Gene Expression Regulation
Genes
Genomics
Head injuries
Health maintenance organizations
Homeostatic plasticity
Immune response
Immune system
Immunoregulation
Immunosuppressive agents
Inflammation
Injury analysis
Injury prevention
Innate immunity
Ischemia
Laboratory animals
Male
Medicine and Health Sciences
Neurodegeneration
Neurodegenerative Diseases - etiology
Neurodegenerative Diseases - metabolism
NF-AT protein
NF-kappa B - metabolism
NF-κB protein
NFATC Transcription Factors - metabolism
Novels
Percussion
Principal Component Analysis
Proteins
Proteostasis
Rats, Sprague-Dawley
Real-Time Polymerase Chain Reaction
Research and Analysis Methods
Risk factors
Signal Transduction
Signaling
Toll-like receptors
Toll-Like Receptors - metabolism
Traumatic brain injury
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Summary:There are no existing treatments for the long-term degenerative effects of traumatic brain injury (TBI). This is due, in part, to our limited understanding of chronic TBI and uncertainty about which proposed mechanisms for long-term neurodegeneration are amenable to treatment with existing or novel drugs. Here, we used microarray and pathway analyses to interrogate TBI-induced gene expression in the rat hippocampus and cortex at several acute, subchronic and chronic intervals (24 hours, 2 weeks, 1, 2, 3, 6 and 12 months) after parasagittal fluid percussion injury. We used Ingenuity pathway analysis (IPA) and Gene Ontology enrichment analysis to identify significantly expressed genes and prominent cell signaling pathways that are dysregulated weeks to months after TBI and potentially amenable to therapeutic modulation. We noted long-term, coordinated changes in expression of genes belonging to canonical pathways associated with the innate immune response (i.e., NF-κB signaling, NFAT signaling, Complement System, Acute Phase Response, Toll-like receptor signaling, and Neuroinflammatory signaling). Bioinformatic analysis suggested that dysregulation of these immune mediators-many are key hub genes-would compromise multiple cell signaling pathways essential for homeostatic brain function, particularly those involved in cell survival and neuroplasticity. Importantly, the temporal profile of beneficial and maladaptive immunoregulatory genes in the weeks to months after the initial TBI suggests wider therapeutic windows than previously indicated.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0214741