Brain Advance Access published online on February 27, 2006
Brain, doi:10.1093/brain/awl044
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1 Department of Neurology, Jack Miller Center for Peripheral Neuropathy, University of Chicago, Chicago, IL, USA
* To whom correspondence should be addressed. Interferon-
Received October 6, 2005
Revised January 24, 2006
Accepted January 27, 2006
Article
Interferon-
Wensheng Lin 1,
April Kemper 2,
Jeffrey L. Dupree 3,
Heather P. Harding 4,
David Ron 4,
and
Brian Popko 1 *
inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress
2 Department of Pathology, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA
3 Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
4 The Skirball Institute, New York University School of Medicine, New York, NY, USA
Brian Popko, E-mail: bpopko{at}neurology.bsd.uchicago.edu
Abstract 
(IFN-) 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- 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- 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- were associated with endoplasmic reticulum (ER) stress in remyelinating oligodendrocytes. Compared with a wild-type genetic background, the presence of IFN- 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- is capable of inhibiting remyelination in demyelinated lesions and that ER stress modulates the response of remyelinating oligodendrocytes to this cytokine.; oligodendrocyte; PERK; remyelination.
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