Brain Advance Access originally published online on February 27, 2006
Brain 2006 129(5):1306-1318; doi:10.1093/brain/awl044
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Interferon-
inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress
1 Department of Neurology, Jack Miller Center for Peripheral Neuropathy, University of Chicago, Chicago, IL, 2 Department of Pathology, Wake Forest University Baptist Medical Center, Winston-Salem, NC, 3 Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA and 4 The Skirball Institute, New York University School of Medicine, New York, NY, USA
Correspondence to: Dr Brian Popko, Jack Miller Center for Peripheral Neuropathy, Department of Neurology, University of Chicago, 5841 South Maryland Avenue MC2030, Chicago, IL 60637, USA E-mail: bpopko{at}neurology.bsd.uchicago.edu
Interferon-
(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.
Key Words:
ER stress; interferon-; oligodendrocyte; PERK; remyelination
Abbreviations:
BIP = binding immunoglobulin protein; CHOP = CAATT enhancer-binding protein homologous protein; DAPI = 4',6-diamidino-2-phenylindole; EAE = experimental autoimmune encephalomyelitis; ELISA = enzyme-linked immunosorbent assay; EM = electron microscope; ER = endoplasmic reticulum; GFAP = glial fibrillary acidic protein; IFN- = interferon-; IL = interleukin; iNOs = inducible nitric oxide synthase; MBP = myelin basic protein; MHC-I = major histocompatibility complex class I; OPCs = oligodendrocyte precursors; PBS = phosphate-buffered saline; PERK = pancreatic ER kinase; p-eIF-2
= phosphorylated eukaryotic translation initiation factor-2; PID = post-immunization day; TNF- = tumour necrosis factor-; tTA = tetracycline-controlled transactivator
Received October 6, 2005. Revised January 24, 2006. Accepted January 27, 2006.
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