Molecular Mechanisms of Oligodendrocyte Injury in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Patel, Jilpa; Balabanov, Roumen

doi:10.3390/ijms130810647

Cited by 53 publications

(48 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, the debris from the dead cells provides abundant self-antigens which continuously reactivate infiltrated T cells. Thus inflammation and cell death constitute a positive feedback loop in CNS autoimmune inflammation 50 . In conclusion, our present in vitro data implicate neurotoxic effects of IL-17 in the pathogenesis of EAE and finding increased numbers of apoptotic cells in EAE tissues of mice with intact Act1 signaling in NG2 glia supports this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Act1 mediates IL-17–induced EAE pathogenesis selectively in NG2+ glial cells

et al. 2013

View full text Add to dashboard Cite

Interleukin 17(IL-17) is a signature cytokine of Th17 cells. We previously reported that deletion of NF-κ B activator 1(Act1), the key transducer of IL-17R signaling, from the neuroectodermal lineage in mice (neurons, oligodendrocytes, astrocytes)results in attenuated severity of experimental autoimmune encephalomyelitis (EAE). Here we examined the cellular basis of this observation. EAE disease course was unaffected by deleting Act1 from neurons or mature oligodendrocytes and Act1 deletion from astrocytes only modestly affected disease course. Deletion of Act1 from NG2+ glia resulted in markedly reduced EAE severity. Furthermore, IL-17 induced characteristic inflammatory mediator expression in NG2+ glial cells. Additionally, IL-17 also exhibited strong inhibitory effects on the maturation of oligodendrocyte lineage cells in vitro and reduced their survival. These data identify NG2+ glia as the major CNS cellular target of IL-17 in EAE. The sensitivity of oligodendrocyte lineage cells to IL-17-mediated toxicity further suggests a direct link between inflammation and neurodegeneration in multiple sclerosis (MS).

show abstract

Section: Discussionmentioning

confidence: 99%

Act1 mediates IL-17–induced EAE pathogenesis selectively in NG2+ glial cells

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Within demyelinating lesions, oligodendrocytes are damaged by inflammation, which consists of both specific autoimmune responses involving T and B lymphocytes and non-specific noxious responses involving activated monocytes, microglia, and astrocytes [3, 4]. These reactions induce secretion of cell-toxic cytokines and the bioactive free radical nitric oxide, which cause oligodendrocyte cell death [5, 6].…”

Section: Introductionmentioning

confidence: 99%

The crucial role of Erk2 in demyelinating inflammation in the central nervous system

Okazaki

Doi

Hayakawa

et al. 2016

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundBrain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation.MethodsWe used the cuprizone-induced demyelinating mouse model. To examine the role of Erk2, we used Nestin-cre-driven Erk2-deficient mice. We also established primary culture of microglia or astrocytes in order to reveal the crosstalk between two cell types and to determine the downstream cascades of Erk2 in astrocytes.ResultsFirst, we found that Erk is especially activated in astrocytes within the corpus callosum before the peak of demyelination (at 4 weeks after the start of cuprizone feeding). Then, we found that in our model, genetic ablation of Erk2 from neural cells markedly preserved myelin structure and motor function as measured by the rota-rod test. While the initial activation of microglia was not altered in Erk2-deficient mice, these mice showed reduced expression of inflammatory mediators at 3–4 model weeks. Furthermore, the subsequent inflammatory glial responses, characterized by accumulation of microglia and reactive astrocytes, were significantly attenuated in Erk2-deficient mice. These data indicate that Erk2 in astrocytes is involved in augmentation of inflammation and gliosis. We also found that activated, cultured microglia could induce Erk2 activation in cultured astrocytes and subsequent production of inflammatory mediators such as Ccl-2.ConclusionsOur results suggest that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Thus, therapies targeting Erk2 function in glial cells may be a promising approach to the treatment of distinct demyelinating diseases.

show abstract

“…Three lymphocytic cell populations mediate the induction of EAE, Th1, and Th17 types of the CD4 + cells, and CD8 + T-lymphocytes, with the CD4 + lymphocytes being the main mediators; after entering the central nervous system, these cells target myelin proteins and mature oligodendrocytes causing myelin degradation, axonal damage, and oligodendrocyte apoptosis (13)(14)(15)(16). The addition of the pertussis toxin to the injection mixture facilitates the migration of the lymphocytes across the blood-brain barrier (17).…”

Section: The Eae Model Of Multiple Sclerosismentioning

confidence: 99%

Experimental In Vivo Models of Multiple Sclerosis: State of the Art

Palumbo

Pellegrini

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

View full text Add to dashboard Cite

Abstract:Multiple sclerosis is a multifactorial and heterogeneous neurological disease; hence, several experimental animal models had to be developed to mimic the different features of human pathology. Three main classes of animal models have been developed:experimental autoimmune encephalomyelitis (EAE), cuprizone intoxication, and Theiler' s murine encephalomyelitis virus (TMEV) infection. The EAE model is the most versatile as it allows the reproduction of different patterns of multiple sclerosis; it is mostly relevant for relapsing-remitting multiple sclerosis and has allowed the development of several first-line, disease-modifying drugs for the treatment of multiple sclerosis. The other two models are less flexible than the EAE model and, to date, have not led to the discovery of any clinically relevant therapies. The cuprizone model mostly mimics the acute and chronic courses of multiple sclerosis, and it may represent a useful tool to develop novel therapies to protect oligodendrocytes and stimulate remyelination. Finally, the TMEV infection is the reference model to specifically study viral-mediated mechanisms of acute and primary progressive multiple sclerosis. In Vivo Models of Multiple Sclerosis 174

show abstract

Molecular Mechanisms of Oligodendrocyte Injury in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Cited by 53 publications

References 68 publications

Act1 mediates IL-17–induced EAE pathogenesis selectively in NG2+ glial cells

Act1 mediates IL-17–induced EAE pathogenesis selectively in NG2+ glial cells

The crucial role of Erk2 in demyelinating inflammation in the central nervous system

Experimental In Vivo Models of Multiple Sclerosis: State of the Art

Contact Info

Product

Resources

About