title: Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge.
abstract: BACKGROUND
  Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation.
  
  
  RESULTS
  To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1-9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs).
  
  
  CONCLUSIONS
  We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.
authors.affiliation: BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA Phoenix Veteran Affairs Healthcare System, Phoenix, AZ, USA.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Rowe
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Ellis
authors.affiliation: BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA Arizona State University, Tempe, AZ, USA.
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Harrison
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Corder
authors.affiliation: Department of Anatomy & Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Taylor
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Francesc
authors.initials: F
authors.lastname: Marti
authors.affiliation: BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA Phoenix Veteran Affairs Healthcare System, Phoenix, AZ, USA Arizona State University, Tempe, AZ, USA jlifshitz@email.arizona.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lifshitz
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000150:complications* / Q000276:immunology*; D006930:Hyperalgesia / Q000209:etiology* / Q000276:immunology*; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
keywords: Traumatic brain injury; hyperalgesia; immunology; pain; regulatory T cells