MHC class II exacerbates demyelination in vivo independently of T cells

Hiremath, Meenaxi M.; Chen, Vivian S.; Suzuki, Kinuko; Ting, Jenny P.Y.; Matsushima, Glenn K.

doi:10.1016/j.jneuroim.2008.06.034

Cited by 71 publications

(74 citation statements)

References 95 publications

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“…Furthermore, cuprizone-induced demyelination is accompanied by robust microglia activation (Hiremath et al, 1998). Activated microglial cells produce inflammatory mediators including cytokines, such as tumor necrosis factor a, interferon gamma, and nitric oxide, which can reduce remyelination (Hiremath et al, 2008). Importantly, we did not observe a difference in microglia activation status between TG2 2/2 and wt mice as shown by comparable Mac3 immunoreactivity.…”

Section: Discussionmentioning

confidence: 50%

Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin‐forming oligodendrocytes during CNS remyelination

Strien

Baron

Bakker

et al. 2011

Glia

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During normal brain development, axons are myelinated by mature oligodendrocytes (OLGs). Under pathological, demyelinating conditions within the central nervous system (CNS), axonal remyelination is only partially successful because oligodendrocyte precursor cells (OPCs) largely remain in an undifferentiated state resulting in a failure to generate myelinating OLGs. Tissue Transglutaminase (TG2) is a multifunctional enzyme, which amongst other functions, is involved in cell differentiation. Therefore, we hypothesized that TG2 contributes to differentiation of OPCs into OLGs and thereby stimulates remyelination. In vivo studies, using the cuprizone model for de- and remyelination in TG2(-/-) and wild-type mice, showed that during remyelination expression of proteolipid protein mRNA, as a marker for remyelination, in the corpus callosum lags behind in TG2(-/-) mice resulting in less myelin formation and, moreover, impaired recovery of motor behavior. Subsequent in vitro studies showed that rat OPCs express TG2 protein and activity which reduces when the cells have matured into OLGs. Furthermore, when TG2 activity is pharmacologically inhibited, the differentiation of OPCs into myelin-forming OLGs is dramatically reduced. We conclude that TG2 plays a prominent role in remyelination of the CNS, probably through stimulating OPC differentiation into myelin-forming OLGs. Therefore, manipulating TG2 activity may represent an interesting new target for remyelination in demyelinating diseases.

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Section: Discussionmentioning

confidence: 50%

Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin‐forming oligodendrocytes during CNS remyelination

Strien

Baron

Bakker

et al. 2011

Glia

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“…However, the pathological mechanisms in the cuprizone model are different from the autoimmune EAE based on activated encephalitogenic T cells. Only a negligible amount of peripheral immune cells infiltrate the corpus callosum of cuprizone treated mice, while activated and phagocytosing microglia predominate (Hiremath, Chen, Suzuki, Ting, & Matsushima, 2008; Matsushima & Morell, 2001; Mildner et al, 2007). Therefore, the mechanisms of axonal pathology and recuperation might differ as well.…”

Section: Discussionmentioning

confidence: 99%

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

Schultz

Meer

Wrzos

et al. 2017

Glia

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Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de‐ and remyelination, we employed cuprizone‐ and focal lysolecithin‐induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP‐ and SMI32‐ positive damaged axons and the density of SMI31‐positive and silver impregnated preserved axons. Early de‐ and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult.

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“…The cuprizone model has somehow been neglected for a long time by the MS community as a useful tool to study MS pathology. This is, presumably, due to the fact that peripheral immune cells, in particular T and B cells, do not contribute to cuprizone-induced pathology (Acs and Kalman 2012;Hiremath et al 2008;Remington et al 2007), although this point of view has recently been challenged (Kang et al 2012). Nevertheless, the cuprizone model has been more and more established in the past 5 years.…”

Section: Discussionmentioning

confidence: 99%

Anatomical Distribution of Cuprizone-Induced Lesions in C57BL6 Mice

et al. 2015

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Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions occur frequently in the gray matter parts of the brain. Gray matter demyelination and atrophy are found during earliest disease stages, and a growing body of evidence demonstrates a positive correlation between gray matter pathology and various measures of motor disability and cognitive impairment. The cuprizone model is classically regarded as white matter demyelination model. However, recent evidence suggests that different gray matter areas are also affected. In this study, we address the vulnerability of white and gray matter forebrain regions in the cuprizone model. While the corpus callosum as interhemispheric white matter tract is affected in this model, other white matter tracts such as the mammillo-thalamic tract, the columns of the fornix, the stria terminalis, the optic tract, or hippocampal fimbria do not present overt demyelination after 5-week cuprizone intoxication. In contrast, gray matter demyelination is widespread in this model. Furthermore, vulnerable white matter tracts display extensive acute axonal damage. These results highlight the relevance of the cuprizone model to study MS-related gray matter pathology and neurodegeneration.

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MHC class II exacerbates demyelination in vivo independently of T cells

Cited by 71 publications

References 95 publications

Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin‐forming oligodendrocytes during CNS remyelination

Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin‐forming oligodendrocytes during CNS remyelination

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

Anatomical Distribution of Cuprizone-Induced Lesions in C57BL6 Mice

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