RT Journal Article
SR Electronic
T1 Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury
JF eneuro
JO eneuro
FD Society for Neuroscience
SP ENEURO.0128-15.2016
DO 10.1523/ENEURO.0128-15.2016
VO 3
IS 1
A1 Karve, Ila P.
A1 Zhang, Moses
A1 Habgood, Mark
A1 Frugier, Tony
A1 Brody, Kate M.
A1 Sashindranath, Maithili
A1 Ek, C. Joakim
A1 Chappaz, Stephane
A1 Kile, Ben T.
A1 Wright, David
A1 Wang, Hong
A1 Johnston, Leigh
A1 Daglas, Maria
A1 Ates, Robert C.
A1 Medcalf, Robert L.
A1 Taylor, Juliet M.
A1 Crack, Peter J.
YR 2016
UL http://www.eneuro.org/content/3/1/ENEURO.0128-15.2016.abstract
AB 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.