Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress.
Interferon-gamma (IFN-gamma) is believed to play a deleterious role in the immune-mediated demyelinating disorder multiple sclerosis. Here we have exploited transgenic mice that ectopically express IFN-gamma in a temporally controlled manner in the CNS to specifically study its effects on remyelination in the cuprizone-induced demyelination model and in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. CNS delivery of IFN-gamma severely suppressed remyelination in both models and impaired the clinical recovery of the mice experiencing EAE. These observations correlated with a dramatic reduction of oligodendroglial repopulation in the demyelinated lesions. Moreover, we found that in cuprizone-treated mice the detrimental actions of IFN-gamma were associated with endoplasmic reticulum (ER) stress in remyelinating oligodendrocytes. Compared with a wild-type genetic background, the presence of IFN-gamma in mice heterozygous for a loss of function mutation in the pancreatic ER kinase (PERK), a kinase that responds specifically to ER stress, further reduced the percentage of remyelinated axons and oligodendrocyte numbers in cuprizone-induced demyelinated lesions. Thus, these data suggest that IFN-gamma is capable of inhibiting remyelination in demyelinated lesions and that ER stress modulates the response of remyelinating oligodendrocytes to this cytokine.
Lin
Wensheng
W
Department of Neurology, Jack Miller Center for Peripheral Neuropathy, University of Chicago, Chicago, IL 60637, USA.
Kemper
April
A
Dupree
Jeffrey L
JL
Harding
Heather P
HP
Ron
David
D
Popko
Brian
B
D000818:Animals; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000276:immunology*; D005260:Female; D007371:Interferon-gamma / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000503:physiopathology; D009186:Myelin Sheath / Q000502:physiology*; D009416:Nerve Regeneration / Q000276:immunology*; D009836:Oligodendroglia / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013312:Stress, Physiological / Q000503:physiopathology; D019892:eIF-2 Kinase / Q000378:metabolism
D003471:Cuprizone; D007371:Interferon-gamma; D019892:eIF-2 Kinase