Gene Expression in Brain during Cuprizone-Induced Demyelination and Remyelination

Morell, Pierre; Barrett, Cheri; Mason, Jeffrey L.; Toews, Arrel D.; Hostettler, Janell; Knapp, Geremy W.; Matsushima, Glenn K.

doi:10.1006/mcne.1998.0715

Cited by 190 publications

(203 citation statements)

References 30 publications

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“…Nonetheless, it has been shown that phagocytosis of apoptotic cells and myelin debris renders microglia/ macrophages supportive of regenerative processes (Bechmann et al, 2001;Boven et al, 2006;Savill et al, 2002). Based on the wide abundance of ORO positive microglia in the corpus callosum in our model and the significant upregulation of lysozyme (a marker for phagocytic microglia; Morell et al, 1998), we propose that ingestion of tissue debris might be one of the triggers for the development of the microglia phenotype in question. It remains to be elucidated, however, whether the microglia phenotype induced by the ingestion of myelin and apoptotic cells is truly supportive of remyelination, or simply permissive.…”

Section: Discussionmentioning

confidence: 72%

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Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

319

270

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In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelinationsupportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. V

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Section: Discussionmentioning

confidence: 72%

“…Several studies have applied microarray analysis to investigate gene expression changes associated with de-myelination and remyelination (Arnett et al, 2003;Jurevics et al, 2002;Morell et al, 1998). These studies were, however, to a certain extent tainted by the use of whole tissue lysates.…”

Section: Discussionmentioning

confidence: 99%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

319

270

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“…Acute demyelination was induced in WT B6 mice as described (21). In this model, demyelination shows a highly reproducible time course of pathological and gene expression changes (21,22,26,27). Severe demyelination Figure 1.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia

et al. 2017

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“…In this model, the vast majority of activated MPs are endogenous microglia, not peripheral macrophages (49)(50)(51)(52). At W4 of CPZ, proinflammatory MPs in the corpus callosum express the phagocytic marker CD11b and are responsible for the phagocytosis of myelin debris (53,54). This supportive action of MPs is an essential step for subsequent remyelination at W6 and W6 + W6 recovery (49,55).…”

Section: Discussionmentioning

confidence: 99%

Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Guglielmetti

Najac

Didonna

et al. 2017

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

133

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Proinflammatory mononuclear phagocytes (MPs) play a crucial role in the progression of multiple sclerosis (MS) and other neurodegenerative diseases. Despite advances in neuroimaging, there are currently limited available methods enabling noninvasive detection of MPs in vivo. Interestingly, upon activation and subsequent differentiation toward a proinflammatory phenotype MPs undergo metabolic reprogramming that results in increased glycolysis and production of lactate. Hyperpolarized (HP) 13 C magnetic resonance spectroscopic imaging (MRSI) is a clinically translatable imaging method that allows noninvasive monitoring of metabolic pathways in real time. This method has proven highly useful to monitor the Warburg effect in cancer, through MR detection of increased HP [1-13 C]pyruvate-tolactate conversion. However, to date, this method has never been applied to the study of neuroinflammation. Here, we questioned the potential of 13 C MRSI of HP [1-13 C]pyruvate to monitor the presence of neuroinflammatory lesions in vivo in the cuprizone mouse model of MS. First, we demonstrated that 13 C MRSI could detect a significant increase in HP [1-13 C]pyruvate-to-lactate conversion, which was associated with a high density of proinflammatory MPs. We further demonstrated that the increase in HP [1-13 C]lactate was likely mediated by pyruvate dehydrogenase kinase 1 up-regulation in activated MPs, resulting in regional pyruvate dehydrogenase inhibition. Altogether, our results demonstrate a potential for 13 C MRSI of HP [1-13 C]pyruvate as a neuroimaging method for assessment of inflammatory lesions. This approach could prove useful not only in MS but also in other neurological diseases presenting inflammatory components.hyperpolarized 13 C MR spectroscopy | multiple sclerosis | neuroinflammation | metabolism | macrophages M ultiple sclerosis (MS) is a multifaceted disorder of the CNS and is one of the most common causes of neurological disability in young adults (1, 2). Cortical and white-matter demyelination occurs early in MS pathogenesis and has been associated with disease progression and subsequent cognitive impairment (3). In the vast majority of cases, demyelinating lesions present a high inflammatory component, with elevated density of activated microglia/macrophages (mononuclear phagocytes, MPs) (4-6). Importantly, evidence suggests that proinflammatory MPs are one of the most abundant sources of reactive oxygen species (7), which mediate demyelination and axonal injury (8). Due to their central role in MS pathogenesis, noninvasive imaging of proinflammatory MPs would be of high importance for monitoring progression and response to antiinflammatory therapeutic approaches.Several recent studies have demonstrated that, upon activation and differentiation toward a proinflammatory phenotype, MPs undergo metabolic reprogramming toward enhanced glucose uptake and increased glycolysis (9-14). As for the Warburg effect observed in cancer cells, this augmented glycolysis takes place under aerobic conditions and results in the...

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Gene Expression in Brain during Cuprizone-Induced Demyelination and Remyelination

Cited by 190 publications

References 30 publications

Identification of a microglia phenotype supportive of remyelination

Identification of a microglia phenotype supportive of remyelination

Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia

Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

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Gene Expression in Brain during Cuprizone-Induced Demyelination and Remyelination

Cited by 190 publications

References 30 publications

Identification of a microglia phenotype supportive of remyelination

Identification of a microglia phenotype supportive of remyelination

Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

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Product

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Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model