Increased demyelination and axonal damage in metallothionein I+II-deficient mice during experimental autoimmune encephalomyelitis

Penkowa, Milena; Espejo, Carmen; Martínez-Cáceres, Eva; Montalbán, Xavier; Hidalgo, Juan

doi:10.1007/s000180300013

Cited by 41 publications

(27 citation statements)

References 64 publications

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“…Together with the Zn-MT2 treatment resulting in EAE reduction, this result implicates that MTs have a strong neuroprotective effect within the CNS (28). Moreover, in the absence of MTs, mice exhibited enhanced production of proinflammatory cytokines such as IL-1 and TNF-α, which in turn can lead to inhibition of leukocyte recruitment and ameliorate EAE (29,30). In this study, we established the correlation between MTs and IL-10 production within Tr1 cells and their proinflammatory role in the EAE model.…”

Section: Discussionmentioning

confidence: 81%

Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Pot

Apétoh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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IL-27–induced type 1 regulatory T (Tr1) cells suppress autoimmunity by producing IL-10. Signal transducer and activator of transcription (STAT) 1 and STAT3 have been described as key transcription factors that promote IL-10 secretion from Tr1 cells induced by IL-27. However, the molecular pathways for negatively regulating Tr1 cell differentiation remain elusive. Here, we show that IL-27 induces metallothioneins (MTs) that in turn prevent Tr1 cell development. MT expression leads to the reduction of STAT1 and STAT3 phosphorylation under Tr1 differentiation condition, resulting in impaired IL-10 production. Accordingly, Tr1 cells derived from MT-deficient mice showed an increased ability to produce IL-10 and potently suppress experimental autoimmune encephalomyelitis upon adoptive transfer. Moreover, activation of STAT1 and/or STAT3 can overcome the suppression of IL-10 by MTs, indicating a dynamic balance between STATs and MTs in regulating IL-10 during Tr1 cell differentiation.

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Section: Discussionmentioning

confidence: 81%

Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Pot

Apétoh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…CZ produces alterations that are very similar to those exhibited by animal models with an experimental autoimmune encephalomyelitis mimicking the demyelinating human disease multiple sclerosis. With this animal model, a protective role of MT-I/II could be demonstrated, since exogenous administration of the protein significantly prevented demyelination and axonal damage while such effects were significantly increased in MT-I/II-deficient mice [23,24]. Thus, the increase in MT-I/II levels in CZ-treated mice can be related to the defence mechanism against CZ toxicity.…”

Section: Discussionmentioning

confidence: 82%

Copper and zinc dismetabolism in the mouse brain upon chronic cuprizone treatment

Zatta

Raso

Zambenedetti³

et al. 2005

CMLS, Cell. Mol. Life Sci.

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Recent reports describe successful treatment using copper chelation therapy in neurodegenerative animal models. However, the success claimed for chelation therapy in neurodegenerative diseases is still rather controversial. To acquire new information on copper metabolism/homeostasis, we utilized cuprizone, a very sensitive and selective copper-chelating agent with well-known neurotoxic properties, as a relevant chemical model in mice. Upon cuprizone treatment, mice developed a pronounced astrocytosis, with brain oedema and spongiosis characterised by vacuolisations of the neuropil predominantly in the white matter. In addition, cuprizone treatment severely altered copper and zinc homeostasis in the central nervous system (CNS) as well as in all other tissues examined, with increasing metal ion concentrations particularly in the CNS. Concomitant with this increase in the Cu and Zn concentration in the brain, metallothionein-I and -II were also highly immunoreactive in astrocyte, consistent with the astrocytosis and demyelination observed in our and other laboratories.

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“…This allowed one to extend the possible spectrum of functions of MT-III protein in the CNS. In addition, studies carried out over the past 10 years showed that genes MT-І and MT-ІІ are expressed in a number of tissues, including those in the CNS, while the expression of genes MT-ІІІ and MT-ІV is characterized by a clear cell specificity [4,5,20].…”

Section: Classification Of Metallothioneinsmentioning

confidence: 98%

Peculiarities of the Molecular Structure and Functions of Metallothioneins in the Central Nervous System

Ушакова

Kruchinenko

2009

Neurophysiology

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This review presents modern concepts on the structure and principles of classification of low-molecularweight proteins capable of binding with metal ions, metallothioneins (MTs). The mechanism underlying the binding of metals with these biopolymers is characterized; the main functions of MTs in the CNS, their role in defense reactions of neurons and other cells, as well as of those of the organism in general are reviewed.

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Increased demyelination and axonal damage in metallothionein I+II-deficient mice during experimental autoimmune encephalomyelitis

Cited by 41 publications

References 64 publications

Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Copper and zinc dismetabolism in the mouse brain upon chronic cuprizone treatment

Peculiarities of the Molecular Structure and Functions of Metallothioneins in the Central Nervous System

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