Chemical hypoxia‐induced integrated stress response activation in oligodendrocytes is mediated by the transcription factor nuclear factor (erythroid‐derived 2)‐like 2 (<scp>NRF</scp>2)

Teske, Nico; Liessem, Annette; Fischbach, Felix; Clarner, Tim; Beyer, Cordian; Wruck, Christoph Jan; Fragoulis, Athanassios; Tauber, Simone C.; Victor, Marion; Kipp, Markus

doi:10.1111/jnc.14270

Cited by 15 publications

(19 citation statements)

References 90 publications

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“…SA is a potent inhibitor of the mitochondrial respiratory chain and inhibits the mitochondrial complex IV which is responsible for the transfer of cytochrome c to an oxygen molecule (Bennett, Mlady et al 1996, Teske, Liessem et al 2018. To induce a breakdown of the mitochondrial inner transmembrane potential (i.e.…”

Section: Sodium Azide Induces Stress In Oligodendroglial Cellsmentioning

confidence: 99%

“…To induce a breakdown of the mitochondrial inner transmembrane potential (i.e. sub-lethal mitochondrial stress reaction), the oligodendroglial cell line OLN93 was stimulated with 10 mM sodium azide (SA) for 24 h as previously described by Teske et al (Teske, Liessem et al 2018 figure 1A). SA-induced LDH release was paralleled by a trend towards lower levels of metabolic activity in these cells (right histogram in figure 1A) however this difference was not statistically significant.…”

Section: Sodium Azide Induces Stress In Oligodendroglial Cellsmentioning

confidence: 99%

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Mitochondrial Impairment in Oligodendroglial Cells Induces Cytokine Expression and Signaling

et al. 2018

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Widespread inflammatory lesions within the central nervous system grey and white matter are major hallmarks of multiple sclerosis. The development of full-blown demyelinating multiple sclerosis lesions might be preceded by preactive lesions which are characterized by focal microglia activation in close spatial relation to apoptotic oligodendrocytes. In this study, we investigated the expression of signaling molecules of oligodendrocytes that might be involved in initial microglia activation during preactive lesion formation. Sodium azide was used to trigger mitochondrial impairment and cellular stress in oligodendroglial cells in vitro. Among various chemokines and cytokines, IL6 was identified as a possible oligodendroglial cell-derived signaling molecule in response to cellular stress. Relevance of this finding for lesion development was further explored in the cuprizone model by applying shortterm cuprizone feeding (2-4 d) on male C57BL/6 mice and subsequent analysis of gene expression, in situ hybridization and histology. Additionally, we analyzed the possible signaling of stressed oligodendroglial cells in vitro as well as in the cuprizone mouse model. In vitro, conditioned medium of stressed oligodendroglial cells triggered the activation of microglia cells. In cuprizone-fed animals, IL6 expression in oligodendrocytes was found in close vicinity of activated microglia cells. Taken together, our data supports the view that stressed oligodendrocytes have the potential to activate microglia cells through a specific cocktail of chemokines and cytokines among IL6. IL6. Further studies will have to identify the temporal activation pattern of these signaling molecules, their cellular sources and impact on neuroinflammation.

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Section: Sodium Azide Induces Stress In Oligodendroglial Cellsmentioning

confidence: 99%

Section: Sodium Azide Induces Stress In Oligodendroglial Cellsmentioning

confidence: 99%

Mitochondrial Impairment in Oligodendroglial Cells Induces Cytokine Expression and Signaling

et al. 2018

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“…Transfection was conducted by using jetPEI® (Polypus Transfection™, #101) transfection reagent according to the manufacturer´s instruction (Teske et al 2018). For transduction, cells were re-plated on poly-D-lysin coated culture dishes in SATO supplemented with 2% FBS.…”

Section: Gene Silencingmentioning

confidence: 99%

“…After positive selection, the gene expression levels of Nrf2 and Keap1 were measured by qRT-PCR to determine knockdown efficiency. Control cells were transduced with a pLKO.1 construct expressing a shRNA without any target in mammals (pLKO.1-shNonTarget; #SHC216) to avoid data misinterpretation based on transduction side effects (Teske et al 2018).…”

Section: Gene Silencingmentioning

confidence: 99%

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Nrf2 Signaling in Sodium Azide-Treated Oligodendrocytes Restores Mitochondrial Functions

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Mitochondrial dysfunctions mark a critical step in many central nervous system (CNS) pathologies, including multiple sclerosis (MS). Such dysfunctions lead to depolarization of mitochondrial membranes and imbalanced redox homeostasis. In this context, reactive oxygen species (ROS) are potentially deleterious but can also act as an important signaling step for cellular maintenance. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the key regulator in the cellular oxidative stress-response, induces a battery of genes involved in repair and regeneration. Here, we investigated the relevance of Nrf2 signaling for the prevention of cellular damage caused by dysfunctional mitochondria. We employed sodium azide (SA) as mitochondrial inhibitor on oligodendroglial OliNeu cells in vitro, and the cuprizone model with wild type and GFAP-Cre::Keap1 mice to induce mitochondrial defects. The importance of Nrf2 for cellular functions and survival after SA treatment was elucidated by in vitro knockdown experiments with shRNA directed against Nrf2 and its inhibitor Keap1 as well as by methysticin treatment. Metabolic activity, cytotoxicity, and depolarization of the mitochondrial membrane were analyzed after SA treatment. The expression of Nrf2 target genes as well as endoplasmic reticulum stress response genes was additionally measured by real-time PCR (in vitro) and PCR gene arrays (in vivo). Treatment of OliNeu cells with SA resulted in significant depolarization of the mitochondrial membrane, decreased metabolic activity, and increased cytotoxicity. This was partly counteracted in Nrf2-hyperactivated cells and intensified in Nrf2-knockdown cells. Our studies demonstrate a key role of Nrf2 in maintaining cellular functions and survival in the context of mitochondrial dysfunction.

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Cuprizone‐induced graded oligodendrocyte vulnerability is regulated by the transcription factor DNA damage‐inducible transcript 3

Fischbach¹,

Nedelcu²,

Leopold³

et al. 2018

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Oligodendrocytes are integral to efficient neuronal signaling. Loss of myelinating oligodendrocytes is a central feature of many neurological diseases, including multiple sclerosis (MS). The results of neuropathological studies suggest that oligodendrocytes react with differing sensitivity to toxic insults, with some cells dying early during lesion development and some cells being resistant for weeks. This proposed graded vulnerability has never been demonstrated but provides an attractive window for therapeutic interventions. Furthermore, the biochemical pathways associated with graded oligodendrocyte vulnerability have not been well explored. We used immunohistochemistry and serial block‐face scanning electron microscopy (3D‐SEM) to show that cuprizone‐induced metabolic stress results in an “out of phase” degeneration of oligodendrocytes. Although expression induction of stress response transcription factors in oligodendrocytes occurs within days, subsequent oligodendrocyte apoptosis continues for weeks. In line with the idea of an out of phase degeneration of oligodendrocytes, detailed ultrastructural reconstructions of the axon–myelin unit demonstrate demyelination of single internodes. In parallel, genome wide array analyses revealed an active unfolded protein response early after initiation of the cuprizone intoxication. In addition to the cytoprotective pathways, the pro‐apoptotic transcription factor DNA damage‐inducible transcript 3 (DDIT3) was induced early in oligodendrocytes. In advanced lesions, DDIT3 was as well expressed by activated astrocytes. Toxin‐induced oligodendrocyte apoptosis, demyelination, microgliosis, astrocytosis, and acute axonal damage were less intense in the Ddit3‐null mutants. This study identifies DDIT3 as an important regulator of graded oligodendrocyte vulnerability in a MS animal model. Interference with this stress cascade might offer a promising therapeutic approach for demyelinating disorders.

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Chemical hypoxia‐induced integrated stress response activation in oligodendrocytes is mediated by the transcription factor nuclear factor (erythroid‐derived 2)‐like 2 (NRF2)

Cited by 15 publications

References 90 publications

Mitochondrial Impairment in Oligodendroglial Cells Induces Cytokine Expression and Signaling

Mitochondrial Impairment in Oligodendroglial Cells Induces Cytokine Expression and Signaling

Nrf2 Signaling in Sodium Azide-Treated Oligodendrocytes Restores Mitochondrial Functions

Cuprizone‐induced graded oligodendrocyte vulnerability is regulated by the transcription factor DNA damage‐inducible transcript 3

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