Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice

Hiremath, Meenaxi M.; Saito, Yuriko; Knapp, Geremy W.; Ting, Jenny P.-Y.; Suzuki, Kinuko; Matsushima, Glenn K.

doi:10.1016/s0165-5728(98)00168-4

Cited by 364 publications

(531 citation statements)

References 34 publications

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“…As shown in Fig. 4E, serum lactate levels were significantly increased at W4 and W6 of CPZ (161 ± 62% W4 P = 0.0014; 166 ± 48% W6 P = 0.0007) and returned to CTRL levels by the end of the recovery period (P = 0.0024), confirming the systemic effect of CPZ diet (38,44,45). To confirm that the production of HP [1-13 C]lactate was driven by the presence of MPs into the corpus callosum following CPZ diet, we studied CX 3 CR1 GFP/GFP mice, which exhibit highly reduced or absent microgliosis, astrogliosis, and demyelination at W4 of CPZ diet, as previously described (39).…”

Section: Resultssupporting

confidence: 66%

“…We conducted a longitudinal study of the toxin-induced cuprizone (CPZ) mouse model, a well-established MS model characterized by high spatial and temporal reproducibility of neuroinflammatory lesions (37,38). Our results demonstrated a significant increase in HP [1-13 C]pyruvate-to-lactate conversion in the corpus callosum of CPZ mice as detected by 13 C MRSI at 14.1 T. Using immunofluorescence, we then showed that increased HP [1-13 C]lactate production was associated with a high density of activated proinflammatory MPs that overexpressed PDK1.…”

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confidence: 99%

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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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Section: Resultssupporting

confidence: 66%

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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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“…To investigate drainage routes from the brain to the CLN, we used different non-inflammatory CNS damage models [31,33,[44][45][46]. In cuprizone-treated animals, numerous cells containing myelin antigens were observed in the deep CLN, whereas such cells were observed only occasionally in the superficial CLN.…”

Section: Discussionmentioning

confidence: 99%

“…3b,c), reflecting the mild CNS damage in these models [44,45]. The cuprizone model is characterized by extensive CNS demyelination induced by cuprizone, which selectively kills oligodendrocytes [33]. Little drainage of the myelin antigen PLP to the superficial CLN was noticed (Fig.…”

Section: Drainage Of Cns Antigens To the Cns-draining Lymph Nodes Is mentioning

confidence: 94%

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Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in J Mol Med (2009) human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked.

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Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination

et al. 2000

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We have documented changes in the oligodendrocyte population during demyelinating insult to the adult CNS. Feeding of cuprizone to adult mice led to apoptotic death of mature oligodendrocytes followed by profound demyelination of the corpus callosum. A regenerative response was initiated even during active demyelination. Oligodendrocyte progenitors have begun to proliferate and then accumulate within the lesion. Many of these cells may have migrated from the sub‐ventricular zone and fornix before their accumulation in the demyelinating corpus callosum. The accumulation of differentiating oligodendrocyte progenitors was followed closely by the reappearance of mature oligodendrocytes and remyelination. Interestingly, an increase in IGF‐1 mRNA was detected at Week 3 through Week 7, suggesting potential involvement in remyelination. Other factors, however, such as PDGF, NT3, FGF, jagged, and notch remained unchanged. These results suggest that the mature oligodendroglial population depleted by apoptosis is replaced by a newly formed oligodendroglial population derived from progenitors; these accumulate and seem to differentiate during remyelination. J. Neurosci. Res. 61:251–262, 2000. © 2000 Wiley‐Liss, Inc.

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Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice

Cited by 364 publications

References 34 publications

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

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

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination

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Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice

Cited by 364 publications

References 34 publications

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

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

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination

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

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