title: Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis.
abstract: The Type I interferons (IFN), beta (IFN-β) and the alpha family (IFN-α), act through a common receptor and have anti-inflammatory effects. IFN-β is used to treat multiple sclerosis (MS) and is effective against experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice with EAE show elevated levels of Type I IFNs in the central nervous system (CNS), suggesting a role for endogenous Type I IFN during inflammation. However, the therapeutic benefit of Type I IFN produced in the CNS remains to be established. The aim of this study was to examine whether experimentally induced CNS-endogenous Type I IFN influences EAE. Using IFN-β reporter mice, we showed that direct administration of polyinosinic-polycytidylic acid (poly I:C), a potent inducer of IFN-β, into the cerebrospinal fluid induced increased leukocyte numbers and transient upregulation of IFN-β in CD45/CD11b-positive cells located in the meninges and choroid plexus, as well as enhanced IFN-β expression by parenchymal microglial cells. Intrathecal injection of poly I:C to mice showing first symptoms of EAE substantially increased the normal disease-associated expression of IFN-α, IFN-β, interferon regulatory factor-7 and IL-10 in CNS, and disease worsening was prevented for as long as IFN-α/β was expressed. In contrast, there was no therapeutic effect on EAE in poly I:C-treated IFN receptor-deficient mice. IFN-dependent microglial and astrocyte response included production of the chemokine CXCL10. These results show that Type I IFN induced within the CNS can play a protective role in EAE and highlight the role of endogenous type I IFN in mediating neuroprotection.
authors: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 25, 5000, Odense C, Denmark.
authors: Reza
authors: R
authors: Khorooshi
authors: Marlene Thorsen
authors: MT
authors: Mørch
authors: Thomas Hellesøe
authors: TH
authors: Holm
authors: Carsten Tue
authors: CT
authors: Berg
authors: Ruthe Truong
authors: RT
authors: Dieu
authors: Dina
authors: D
authors: Dræby
authors: Shohreh
authors: S
authors: Issazadeh-Navikas
authors: Siegfried
authors: S
authors: Weiss
authors: Stefan
authors: S
authors: Lienenklaus
authors: Trevor
authors: T
authors: Owens
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D054357:Chemokine CXCL10 / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008578:Meninges / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011070:Poly I-C / Q000494:pharmacology*; D011897:Random Allocation; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C508032:Ifnar1 protein, mouse; D016898:Interferon-alpha; D018696:Neuroprotective Agents; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D011070:Poly I-C