Interferon-γ inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress

Abstract

Interferon-γ (IFN-γ) 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-γ 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-γ 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-γ were associated with endoplasmic reticulum (ER) stress in remyelinating oligodendrocytes. Compared with a wild-type genetic background, the presence of IFN-γ 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-γ is capable of inhibiting remyelination in demyelinated lesions and that ER stress modulates the response of remyelinating oligodendrocytes to this cytokine.

ER stress, interferon-γ, oligodendrocyte, PERK, remyelination

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-γ = interferon-γ, 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-2α = phosphorylated eukaryotic translation initiation factor-2α, PID = post-immunization day, TNF-α = tumour necrosis factor-α, tTA = tetracycline-controlled transactivator