title: The interdependent, overlapping, and differential roles of type I and II IFNs in the pathogenesis of experimental autoimmune encephalomyelitis.
abstract: Type I IFNs (IFN-α and IFN-β) and type II IFN (IFN-γ) mediate both regulation and inflammation in multiple sclerosis, neuromyelitis optica, and in experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanism for these Janus-like activities of type I and II IFNs in neuroinflammation remains unclear. Although endogenous type I IFN signaling provides a protective response in neuroinflammation, we find that when IFN-γ signaling is ablated, type I IFNs drive inflammation, resulting in exacerbated EAE. IFN-γ has a disease stage-specific opposing function in EAE. Treatment of mice with IFN-γ during the initiation phase of EAE leads to enhanced severity of disease. In contrast, IFN-γ treatment during the effector phase attenuated disease. This immunosuppressive activity of IFN-γ required functional type I IFN signaling. In IFN-α/β receptor-deficient mice, IFN-γ treatment during effector phase of EAE exacerbated disease. Using an adoptive transfer EAE model, we found that T cell-intrinsic type I and II IFN signals are simultaneously required to establish chronic EAE by encephalitogenic Th1 cells. However, in Th17 cells loss of either IFN signals leads to the development of a severe chronic disease. The data imply that type I and II IFN signals have independent but nonredundant roles in restraining encephalitogenic Th17 cells in vivo. Collectively, our data show that type I and II IFNs function in an integrated manner to regulate pathogenesis in EAE.
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. rnaves@med.puc.cl
authors: Rodrigo
authors: R
authors: Naves
authors: Simer P
authors: SP
authors: Singh
authors: Kevin S
authors: KS
authors: Cashman
authors: Amber L
authors: AL
authors: Rowse
authors: Robert C
authors: RC
authors: Axtell
authors: Lawrence
authors: L
authors: Steinman
authors: John D
authors: JD
authors: Mountz
authors: Chad
authors: C
authors: Steele
authors: Patrizia
authors: P
authors: De Sarno
authors: Chander
authors: C
authors: Raman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D007370:Interferon Type I; D007371:Interferon-gamma
references: Mult Scler. 1995;1 Suppl 1:S17-21
references: 9345392
references: J Immunol. 2005 Feb 1;174(3):1416-23
references: 15661899
references: Autoimmunity. 1993;16(4):267-74
references: 7517706
references: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7835-40
references: 16682623
references: J Neuroimmunol. 1991 Nov;34(2-3):121-32
references: 1918319
references: Nat Immunol. 2005 Nov;6(11):1123-32
references: 16200070
references: Lancet. 1987 Apr 18;1(8538):893-5
references: 2882294
references: Nat Med. 2010 Apr;16(4):406-12
references: 20348925
references: Eur J Immunol. 1996 Oct;26(10):2393-8
references: 8898951
references: Am J Pathol. 2004 Nov;165(5):1519-33
references: 15509523
references: J Immunol. 1999 Nov 15;163(10):5278-86
references: 10553050
references: J Immunol. 2001 Aug 1;167(3):1821-9
references: 11466408
references: J Neuroimmunol. 1992 Feb;36(2-3):105-15
references: 1732276
references: Nat Rev Immunol. 2009 Jun;9(6):393-407
references: 19444307
references: J Immunol. 2009 Dec 1;183(11):7169-77
references: 19890056
references: Nat Immunol. 2005 Nov;6(11):1133-41
references: 16200068
references: J Neurol Sci. 1990 Dec;100(1-2):37-42
references: 2128520
references: J Neuroimmune Pharmacol. 2012 Mar;7(1):253-65
references: 22012268
references: Annu Rev Immunol. 2003;21:713-58
references: 12500979
references: Nat Med. 2008 Mar;14(3):337-42
references: 18278054
references: J R Coll Physicians Lond. 1999 Jul-Aug;33(4):315-22
references: 10472018
references: J Immunol. 2007 Jul 15;179(2):958-66
references: 17617587
references: J Exp Med. 2008 Oct 27;205(11):2633-42
references: 18852291
references: J Clin Invest. 2008 May;118(5):1680-90
references: 18382764
references: Immunol Cell Biol. 2003 Dec;81(6):459-71
references: 14636243
references: Annu Rev Immunol. 2005;23:307-36
references: 15771573
references: J Virol. 2008 Feb;82(4):1934-45
references: 18057251
references: Exp Mol Pathol. 2010 Oct;89(2):83-91
references: 20599938
references: J Immunol. 2008 Jul 1;181(1):338-45
references: 18566399
references: J Immunol. 2009 Oct 15;183(8):5418-27
references: 19783688
references: J Immunol. 2010 Jun 15;184(12):7047-56
references: 20483775
references: J Exp Med. 2008 Jul 7;205(7):1517-22
references: 18591407
references: J Immunol. 2004 Sep 1;173(5):2928-32
references: 15322150
references: J Immunol. 2006 Mar 15;176(6):3804-12
references: 16517751
references: J Exp Med. 2008 Jul 7;205(7):1535-41
references: 18573909
references: Eur J Immunol. 1996 Jul;26(7):1641-6
references: 8766573
references: J Immunol. 1996 Oct 15;157(8):3223-7
references: 8871615
references: J Neuroimmunol. 1992 Oct;40(2-3):211-8
references: 1430152
references: Pharmacol Ther. 2008 Jan;117(1):77-93
references: 17961662
references: Clin Neurol Neurosurg. 2008 Nov;110(9):951-7
references: 18502570
references: J Exp Med. 2007 Jan 22;204(1):141-52
references: 17227910
references: Nat Med. 2002 Jun;8(6):613-9
references: 12042813
references: Immunity. 2009 Oct 16;31(4):539-50
references: 19833085
references: Ann N Y Acad Sci. 2007 Apr;1103:179-91
references: 17376826
references: Lancet. 2002 Apr 6;359(9313):1221-31
references: 11955556
references: Immunity. 2008 May;28(5):675-86
references: 18424188
references: J Immunol. 2008 Feb 15;180(4):2204-13
references: 18250427
references: J Leukoc Biol. 1988 Dec;44(6):514-20
references: 3142957
references: J Immunol. 1994 Nov 1;153(9):4258-67
references: 7523520
references: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11495-500
references: 20534530
references: Science. 1994 Jun 24;264(5167):1918-21
references: 8009221
references: Neurology. 2007 Jun 12;68(24 Suppl 4):S8-11
references: 17562848
references: J Immunol. 2003 May 1;170(9):4776-84
references: 12707359
references: J Neuroimmunol. 1994 Jan;49(1-2):1-7
references: 8294548
references: PLoS Biol. 2010 Apr 27;8(4):e1000361
references: 20436908
references: PLoS One. 2012;7(12):e52658
references: 23285134
references: J Allergy Clin Immunol. 1998 Aug;102(2):165-9
references: 9723655
references: Nat Rev Drug Discov. 2007 Dec;6(12):975-90
references: 18049472
references: Mol Cell Neurosci. 1998 Dec;12(6):376-89
references: 9888990
references: J Immunol. 1988 Mar 1;140(5):1506-10
references: 3126227
references: Neurology. 1995 Jun;45(6 Suppl 6):S16-21
references: 7540265
references: Ann N Y Acad Sci. 2009 Feb;1153:256-63
references: 19236348
references: Science. 2000 Jun 30;288(5475):2357-60
references: 10875919
references: J Immunol. 1996 Jan 1;156(1):5-7
references: 8598493
references: J Exp Med. 2000 Jul 3;192(1):123-8
references: 10880533
references: Biochimie. 2007 Jun-Jul;89(6-7):899-902
references: 17574320
references: Annu Rev Immunol. 1993;11:571-611
references: 8476573
references: J Immunol. 2000 Dec 15;165(12):7157-63
references: 11120847
references: J Immunol. 2012 Sep 15;189(6):2918-30
references: 22904299
references: Science. 1994 Feb 25;263(5150):1139-43
references: 7509084
references: Clin Exp Immunol. 1990 Aug;81(2):183-8
references: 2117508