title: Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury.
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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne , Parkville, Victoria, Australia , 3010.
authors.forename: Ila P
authors.initials: IP
authors.lastname: Karve
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne , Parkville, Victoria, Australia , 3010.
authors.forename: Moses
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne , Parkville, Victoria, Australia , 3010.
authors.forename: Mark
authors.initials: M
authors.lastname: Habgood
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne , Parkville, Victoria, Australia , 3010.
authors.forename: Tony
authors.initials: T
authors.lastname: Frugier
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne , Parkville, Victoria, Australia , 3010.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Brody
authors.affiliation: Australian Centre for Blood Diseases, Monash University , Melbourne, Victoria, Australia , 3004.
authors.forename: Maithili
authors.initials: M
authors.lastname: Sashindranath
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne , Parkville, Victoria, Australia , 3010.
authors.forename: C Joakim
authors.initials: CJ
authors.lastname: Ek
authors.affiliation: ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria, Australia 3052.
authors.forename: Stephane
authors.identifier: 0000-0003-0574-7544
authors.initials: S
authors.lastname: Chappaz
authors.affiliation: ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria, Australia 3052.
authors.forename: Ben T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: Florey Imaging, The Florey Institute of Neuroscience and Mental Health , Parkville, Victoria, Australia 3052.
authors.forename: David
authors.initials: D
authors.lastname: Wright
authors.affiliation: Florey Imaging, The Florey Institute of Neuroscience and Mental Health , Parkville, Victoria, Australia 3052.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Florey Imaging, The Florey Institute of Neuroscience and Mental Health , Parkville, Victoria, Australia 3052.
authors.forename: Leigh
authors.initials: L
authors.lastname: Johnston
authors.affiliation: Australian Centre for Blood Diseases, Monash University , Melbourne, Victoria, Australia , 3004.
authors.forename: Maria
authors.initials: M
authors.lastname: Daglas
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne , Parkville, Victoria, Australia , 3010.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Ates
authors.affiliation: Australian Centre for Blood Diseases, Monash University , Melbourne, Victoria, Australia , 3004.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Medcalf
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne , Parkville, Victoria, Australia , 3010.
authors.forename: Juliet M
authors.initials: JM
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne , Parkville, Victoria, Australia , 3010.
authors.forename: Peter J
authors.identifier: 0000-0002-5030-0330
authors.initials: PJ
authors.lastname: Crack
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D004660:Encephalitis / Q000209:etiology / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; C508032:Ifnar1 protein, mouse; D018836:Inflammation Mediators; D007370:Interferon Type I; D012333:RNA, Messenger; D053633:Receptor, Interferon alpha-beta
keywords: neuroinflammation; traumatic brain injury; type-1 interferon