Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury

Ila P. Karve, Moses Zhang, Mark Habgood, Tony Frugier, Kate M. Brody, Maithili Sashindranath, C. Joakim Ek, Stephane Chappaz, Ben T. Kile, David Wright, Hong Wang, Leigh Johnston, Maria Daglas, Robert C. Ates, Robert L. Medcalf, Juliet M. Taylor, Peter J. Crack

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8- to 10-week-old male C57BL/6J WT and IFNAR1(-/-) mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1(-/-) mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1(-/-) mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNFα, IL-1β and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI.

Original languageEnglish
Number of pages18
JournaleNeuro
Volume3
Issue number1
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

  • neuroinflammation
  • traumatic brain injury
  • type-1 interferon

Cite this

Karve, Ila P. ; Zhang, Moses ; Habgood, Mark ; Frugier, Tony ; Brody, Kate M. ; Sashindranath, Maithili ; Ek, C. Joakim ; Chappaz, Stephane ; Kile, Ben T. ; Wright, David ; Wang, Hong ; Johnston, Leigh ; Daglas, Maria ; Ates, Robert C. ; Medcalf, Robert L. ; Taylor, Juliet M. ; Crack, Peter J. / Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury. In: eNeuro. 2016 ; Vol. 3, No. 1.
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abstract = "Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8- to 10-week-old male C57BL/6J WT and IFNAR1(-/-) mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1(-/-) mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1(-/-) mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNFα, IL-1β and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI.",
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year = "2016",
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Karve, IP, Zhang, M, Habgood, M, Frugier, T, Brody, KM, Sashindranath, M, Ek, CJ, Chappaz, S, Kile, BT, Wright, D, Wang, H, Johnston, L, Daglas, M, Ates, RC, Medcalf, RL, Taylor, JM & Crack, PJ 2016, 'Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury' eNeuro, vol. 3, no. 1. https://doi.org/10.1523/ENEURO.0128-15.2016

Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury. / Karve, Ila P.; Zhang, Moses; Habgood, Mark; Frugier, Tony; Brody, Kate M.; Sashindranath, Maithili; Ek, C. Joakim; Chappaz, Stephane; Kile, Ben T.; Wright, David; Wang, Hong; Johnston, Leigh; Daglas, Maria; Ates, Robert C.; Medcalf, Robert L.; Taylor, Juliet M.; Crack, Peter J.

In: eNeuro, Vol. 3, No. 1, 01.01.2016.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Karve, Ila P.

AU - Zhang, Moses

AU - Habgood, Mark

AU - Frugier, Tony

AU - Brody, Kate M.

AU - Sashindranath, Maithili

AU - Ek, C. Joakim

AU - Chappaz, Stephane

AU - Kile, Ben T.

AU - Wright, David

AU - Wang, Hong

AU - Johnston, Leigh

AU - Daglas, Maria

AU - Ates, Robert C.

AU - Medcalf, Robert L.

AU - Taylor, Juliet M.

AU - Crack, Peter J.

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