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

Deborah R. Boone, Harris A. Weisz, Hannah E. Willey, Karen E.O. Torres, Michael T. Falduto, Mala Sinha, Heidi Spratt, Ian J. Bolding, Kathea M. Johnson, Margaret A. Parsley, Douglas Dewitt, Donald Prough, Helen Hellmich

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere0214741
JournalPloS one
Volume14
Issue number4
DOIs
StatePublished - Apr 1 2019

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Brain
brain
Genes
Cell signaling
Chronic Brain Injury
Percussion
Gene Expression
Acute-Phase Reaction
Gene Ontology
Neuronal Plasticity
Toll-Like Receptors
Microarray Analysis
gene expression
therapeutics
Computational Biology
genes
Innate Immunity
Uncertainty
Bioinformatics
Microarrays

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Boone, D. R., Weisz, H. A., Willey, H. E., Torres, K. E. O., Falduto, M. T., Sinha, M., ... Hellmich, H. (2019). Traumatic brain injury induces long-lasting changes in immune and regenerative signaling. PloS one, 14(4), [e0214741]. https://doi.org/10.1371/journal.pone.0214741

Traumatic brain injury induces long-lasting changes in immune and regenerative signaling. / 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; Prough, Donald; Hellmich, Helen.

In: PloS one, Vol. 14, No. 4, e0214741, 01.04.2019.

Research output: Contribution to journalArticle

Boone, DR, Weisz, HA, Willey, HE, Torres, KEO, Falduto, MT, Sinha, M, Spratt, H, Bolding, IJ, Johnson, KM, Parsley, MA, Dewitt, D, Prough, D & Hellmich, H 2019, 'Traumatic brain injury induces long-lasting changes in immune and regenerative signaling', PloS one, vol. 14, no. 4, e0214741. https://doi.org/10.1371/journal.pone.0214741
Boone DR, Weisz HA, Willey HE, Torres KEO, Falduto MT, Sinha M et al. Traumatic brain injury induces long-lasting changes in immune and regenerative signaling. PloS one. 2019 Apr 1;14(4). e0214741. https://doi.org/10.1371/journal.pone.0214741
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 ; Prough, Donald ; Hellmich, Helen. / Traumatic brain injury induces long-lasting changes in immune and regenerative signaling. In: PloS one. 2019 ; Vol. 14, No. 4.
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