Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge

Persistent Link:
http://hdl.handle.net/10150/614986
Title:
Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge
Author:
Rowe, R. K.; Ellis, G. I.; Harrison, J. L.; Bachstetter, A. D.; Corder, G. F.; Van Eldik, L. J.; Taylor, B. K.; Marti, F.; Lifshitz, J.
Affiliation:
Univ Arizona, Coll Med Phoenix, Dept Child Hlth
Issue Date:
2016-05-13
Publisher:
SAGE Publications
Citation:
Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge 2016, 12 (0) Molecular Pain
Journal:
Molecular Pain
Rights:
Creative Commons Non Commercial CC-BY-NC: This article is distributed under the terms of the Creative Commons AttributionNonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/).
Collection Information:
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
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.
ISSN:
1744-8069
DOI:
10.1177/1744806916647055
Keywords:
Traumatic brain injury; Pain; hyperalgesia; regulatory T cells; immunology
Version:
Final published version
Sponsors:
NIH [K02 DA19656, R01 DA037621, R01 NS065052, F31 NS09092]; Bisgrove Scholar Award from Science Foundation Arizona; Diane and Bruce Halle Foundation; Office of the Vice President for Research; Markey Cancer Center; NIH Shared Instrument Program [S10 RR026827]
Additional Links:
http://mpx.sagepub.com/lookup/doi/10.1177/1744806916647055

Full metadata record

DC FieldValue Language
dc.contributor.authorRowe, R. K.en
dc.contributor.authorEllis, G. I.en
dc.contributor.authorHarrison, J. L.en
dc.contributor.authorBachstetter, A. D.en
dc.contributor.authorCorder, G. F.en
dc.contributor.authorVan Eldik, L. J.en
dc.contributor.authorTaylor, B. K.en
dc.contributor.authorMarti, F.en
dc.contributor.authorLifshitz, J.en
dc.date.accessioned2016-06-29T01:14:01Z-
dc.date.available2016-06-29T01:14:01Z-
dc.date.issued2016-05-13-
dc.identifier.citationDiffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge 2016, 12 (0) Molecular Painen
dc.identifier.issn1744-8069-
dc.identifier.doi10.1177/1744806916647055-
dc.identifier.urihttp://hdl.handle.net/10150/614986-
dc.description.abstractBackground: 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.en
dc.description.sponsorshipNIH [K02 DA19656, R01 DA037621, R01 NS065052, F31 NS09092]; Bisgrove Scholar Award from Science Foundation Arizona; Diane and Bruce Halle Foundation; Office of the Vice President for Research; Markey Cancer Center; NIH Shared Instrument Program [S10 RR026827]en
dc.language.isoenen
dc.publisherSAGE Publicationsen
dc.relation.urlhttp://mpx.sagepub.com/lookup/doi/10.1177/1744806916647055en
dc.rightsCreative Commons Non Commercial CC-BY-NC: This article is distributed under the terms of the Creative Commons AttributionNonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/).en
dc.subjectTraumatic brain injuryen
dc.subjectPainen
dc.subjecthyperalgesiaen
dc.subjectregulatory T cellsen
dc.subjectimmunologyen
dc.titleDiffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challengeen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Coll Med Phoenix, Dept Child Hlthen
dc.identifier.journalMolecular Painen
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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