Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system.
The action of type I interferons in the central nervous system (CNS) during autoimmunity is largely unknown. Here, we demonstrate elevated interferon beta concentrations in the CNS, but not blood, of mice with experimental autoimmune encephalomyelitis (EAE), a model for CNS autoimmunity. Furthermore, mice devoid of the broadly expressed type I IFN receptor (IFNAR) developed exacerbated clinical disease accompanied by a markedly higher inflammation, demyelination, and lethality without shifting the T helper 17 (Th17) or Th1 cell immune response. Whereas adoptive transfer of encephalitogenic T cells led to enhanced disease in Ifnar1(-/-) mice, newly created conditional mice with B or T lymphocyte-specific IFNAR ablation showed normal EAE. The engagement of IFNAR on neuroectodermal CNS cells had no protective effect. In contrast, absence of IFNAR on myeloid cells led to severe disease with an enhanced effector phase and increased lethality, indicating a distinct protective function of type I IFNs during autoimmune inflammation of the CNS.
Prinz
Marco
M
Department of Neuropathology, University of Freiburg, D-79106 Freiburg, Germany. marco.prinz@uniklinik-freiburg.de
Schmidt
Hauke
H
Mildner
Alexander
A
Knobeloch
Klaus-Peter
KP
Hanisch
Uwe-Karsten
UK
Raasch
Jenni
J
Merkler
Doron
D
Detje
Claudia
C
Gutcher
Ilona
I
Mages
Jörg
J
Lang
Roland
R
Martin
Roland
R
Gold
Ralf
R
Becher
Burkhard
B
Brück
Wolfgang
W
Kalinke
Ulrich
U
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000378:metabolism; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic
D000949:Histocompatibility Antigens Class II; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta