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* Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada;
Department of Pathology, London Health Sciences Centre and University of Western Ontario, London, Ontario, Canada;
Department of Anatomy, Faculty of Medicine, University of Miyazaki, Japan;
Unité Mixte de Recherche, Centre National de la Recherche Scientifique-bioMerieux, l’Institut Fédératif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Superieure de Lyon, Lyon, France; and
¶ Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
Retroviral envelopes are pathogenic glycoproteins which cause neuroinflammation, neurodegeneration, and endoplasmic reticulum stress responses. The human endogenous retrovirus (HERV-W) envelope protein, Syncytin-1, is highly expressed in CNS glia of individuals with multiple sclerosis (MS). In this study, we investigated the mechanisms by which Syncytin-1 mediated neuroimmune activation and oligodendrocytes damage. In brain tissue from individuals with MS, ASCT1, a receptor for Syncytin-1 and a neutral amino acid transporter, was selectively suppressed in astrocytes (p < 0.05). Syncytin-1 induced the expression of the endoplasmic reticulum stress sensor, old astrocyte specifically induced substance (OASIS), in cultured astrocytes, similar to findings in MS brains. Overexpression of OASIS in astrocytes increased inducible NO synthase expression but concurrently down-regulated ASCT1 (p < 0.01). Treatment of astrocytes with a NO donor enhanced expression of early growth response 1, with an ensuing reduction in ASCT1 expression (p < 0.05). Small-interfering RNA molecules targeting Syncytin-1 selectively down-regulated its expression, preventing the suppression of ASCT1 and the release of oligodendrocyte cytotoxins by astrocytes. A Syncytin-1-transgenic mouse expressing Syncytin-1 under the glial fibrillary acidic protein promoter demonstrated neuroinflammation, ASCT1 suppression, and diminished levels of myelin proteins in the corpus callosum, consistent with observations in CNS tissues from MS patients together with neurobehavioral abnormalities compared with wild-type littermates (p < 0.05). Thus, Syncytin-1 initiated an OASIS-mediated suppression of ASCT1 in astrocytes through the induction of inducible NO synthase with ensuing oligodendrocyte injury. These studies provide new insights into the role of HERV-mediated neuroinflammation and its contribution to an autoimmune disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 J.M.A. was supported by a Studentship from the Alberta Heritage Foundation for Medical Research (AHFMR) and Multiple Sclerosis Society of Canada (MSSC). C.P. holds a Canada Research Chair (Tier 1) in Neurological Infection and Immunity and an AHFMR Senior Scholarship. The MSSC and Canadian Institutes for Health Research supported these studies.
2 Address correspondence and reprint requests to Dr. Christopher Power, Departments of Medicine, Medical Microbiology, and Immunology, 611 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, T6G 2S2 Canada. E-mail address: chris.power{at}ualberta.ca
3 Abbreviations used in this paper: MS, multiple sclerosis; ER, endoplasmic reticulum; MuLV, murine leukemia virus; MoMuLV, Moloney MuLV; iNOS, inducible NO synthase; BiP, IgH chain-binding protein; OASIS, old astrocyte specifically induced substance; Egr1, early growth response 1; Iba, ionized calcium-binding adaptor protein; GFAP, glial fibrillary acidic protein; siRNA, small-interfering RNA; CNP, 2', 3'-cyclic nucleotide 3'-phosphodiesterase; Tg, transgenic; Wt, wild type; EGFP, enhanced GFP; MDM, monocyte-derived macrophage; YFP, yellow fluorescent protein; SNP, sodium nitroprusside; CGT, ceramide galactosyltransferase.
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