title: Oxidative tissue injury in multiple sclerosis is only partly reflected in experimental disease models.
abstract: Recent data suggest that oxidative injury may play an important role in demyelination and neurodegeneration in multiple sclerosis (MS). We compared the extent of oxidative injury in MS lesions with that in experimental models driven by different inflammatory mechanisms. It was only in a model of coronavirus-induced demyelinating encephalomyelitis that we detected an accumulation of oxidised phospholipids, which was comparable in extent to that in MS. In both, MS and coronavirus-induced encephalomyelitis, this was associated with massive microglial and macrophage activation, accompanied by the expression of the NADPH oxidase subunit p22phox but only sparse expression of inducible nitric oxide synthase (iNOS). Acute and chronic CD4(+) T cell-mediated experimental autoimmune encephalomyelitis lesions showed transient expression of p22phox and iNOS associated with inflammation. Macrophages in chronic lesions of antibody-mediated demyelinating encephalomyelitis showed lysosomal activity but very little p22phox or iNOS expressions. Active inflammatory demyelinating lesions induced by CD8(+) T cells or by innate immunity showed macrophage and microglial activation together with the expression of p22phox, but low or absent iNOS reactivity. We corroborated the differences between acute CD4(+) T cell-mediated experimental autoimmune encephalomyelitis and acute MS lesions via gene expression studies. Furthermore, age-dependent iron accumulation and lesion-associated iron liberation, as occurring in the human brain, were only minor in rodent brains. Our study shows that oxidative injury and its triggering mechanisms diverge in different models of rodent central nervous system inflammation. The amplification of oxidative injury, which has been suggested in MS, is only reflected to a limited degree in the studied rodent models.
authors.affiliation: Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schuh
authors.forename: Isabella
authors.initials: I
authors.lastname: Wimmer
authors.forename: Simon
authors.initials: S
authors.lastname: Hametner
authors.forename: Lukas
authors.initials: L
authors.lastname: Haider
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Van Dam
authors.forename: Roland S
authors.initials: RS
authors.lastname: Liblau
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Lesley
authors.initials: L
authors.lastname: Probert
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.forename: Monika
authors.initials: M
authors.lastname: Bradl
authors.forename: Don
authors.initials: D
authors.lastname: Mahad
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018352:Coronavirus Infections / Q000276:immunology / Q000473:pathology; D003471:Cuprizone; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology*; D015870:Gene Expression; D007501:Iron / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology / Q000502:physiology; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D016897:Respiratory Burst / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology / Q000637:transplantation
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D008070:Lipopolysaccharides; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D003471:Cuprizone; D007501:Iron