Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy

Zhao, Xiaofeng; Liao, Yuan; Morgan, Shannon; Mathur, Ramkumar; Feustel, Paul J.; Mazurkiewicz, Joseph E.; Jiang, Qian; Chang, Julia W.; Mathern, Gary W.; Adamo, Matthew A.; Ritaccio, Anthony L.; Gruenthal, Michael; Zhu, Xingen; Huang, Yunfei

doi:10.1016/j.celrep.2018.02.004

Cited by 144 publications

(175 citation statements)

References 34 publications

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“…mTOR pathway has been shown to regulate several aspects of microglia function, including cell viability and phagocytosis. For example, inhibition of mTOR significantly reduced the viability of primary cultured microglia (Dello Russo, Lisi, Tringali, & Navarra, ), whereas constitutive activation of mTOR by ablating its upstream suppressor, tuberous sclerosis 1 (TSC1), enhanced phagocytosis in microglia (Zhao et al, ). Conversely, microglia deficient in mTOR pathway showed reduced proinflammatory cytokines and lesion size (D. Li et al, ).…”

Section: Discussionmentioning

confidence: 99%

mTOR‐mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP

Mai

Chen

et al. 2019

Glia

141

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Microglia constantly survey the brain microenvironment and rapidly adopt different phenotypes in response to environmental stimuli. Such dynamic functions require a unique metabolism and bioenergetics. However, little is known about the basic metabolism of microglia and how metabolic changes regulate microglia function. Here, we uncover that microglia activation is accompanied by extensive transcriptional changes in glucose and lipid metabolism‐related genes. Using metabolic flux assays, we found that LPS, a prototype of the pathogen‐associated molecular patterns (PAMPs), significantly enhanced glycolysis but suppressed oxidative phosphorylation (OXPHOS) in primary cultured microglia. By contrast, ATP, a known damage‐associated molecular pattern (DAMPs) that triggers sterile activation of microglia, boosted both glycolysis and OXPHOS. Importantly, both LPS and ATP activated the mechanistic target of rapamycin (mTOR) pathway and enhanced the intracellular reactive oxygen species (ROS). Inhibition of mTOR activity suppressed glycolysis and ROS production in both conditions but exerted different effects on OXPHOS: it attenuated the ATP‐induced elevation of OXPHOS, yet had no impact on the LPS‐induced suppression of OXPHOS. Further, inhibition of mTOR or glycolysis decreased production of LPS‐induced proinflammatory cytokines and ATP‐induced tumor necrosis factor‐α (TNF‐α) and brain derived neurotrophic factor (BDNF) in microglia. Our study reveals a critical role for mTOR in the regulation of metabolic programming of microglia to shape their distinct functions under different states and shed light on the potential application of targeting metabolism to interfere with microglia‐mediated neuroinflammation in multiple disorders.

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Section: Discussionmentioning

confidence: 99%

mTOR‐mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP

Mai

Chen

et al. 2019

Glia

141

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“…Apart from beneficial roles in the development of CNS, microglia can be widely involved in various types of neurological disorders, including stroke (Guruswamy & ElAli, ; Kronenberg et al, ), multiple sclerosis (MS) (Bogie, Stinissen, & Hendriks, ; Luo et al, ), AD (Hansen, Hanson, & Sheng, ; Sarlus & Heneka, ), PD (Subramaniam & Federoff, ), sleep disorders (Nadjar, Wigren, & Tremblay, ), amyotrophic lateral sclerosis (ALS) (Geloso et al, ; Liu & Wang, ), Huntington's disease (H. M. Yang, Yang, Huang, Tang, & Guo, ), epilepsy (Eyo, Murugan, & Wu, ; Zhao, Liao, et al, ), gliomas (Hambardzumyan, Gutmann, & Kettenmann, ; Schiffer, Mellai, Bovio, & Annovazzi, ), Prion diseases (Aguzzi & Zhu, ; Obst, Simon, Mancuso, & Gomez‐Nicola, ), psychiatric disorders (Mondelli, Vernon, Turkheimer, Dazzan, & Pariante, ; Prinz & Priller, ; Setiawan et al, ; Singhal & Baune, ), neuropathic pain (Inoue & Tsuda, ; Peng et al, ), adrenomyeloneuropathy (Gong et al, ), and traumatic brain injury (Donat, Scott, Gentleman, & Sastre, ). In general, microglia can be rapidly activated depending upon different stimulatory contexts and environmental changes through diverse molecular and cellular programs, subsequently transforming into the activated state and enhancing the expression of the Toll‐like receptors which sensitively bind microbial structures (Arcuri et al, ).…”

Section: The Role Of Microglia In Neurological Diseases: Friend or Foe?mentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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“…SD neuropathology involves neuronal loss, the presence of increased numbers of activated microglia—the brain's macrophages— and astrocytes (Jeyakumar et al, ; Myerowitz et al, ; Sargeant et al, ). Expansion of both microglia and astrocyte numbers are in fact found in many brain disorders including epilepsy, other LSDs, multiple sclerosis, and neurodegenerative disorders, and likely play a role in pathogenesis (Fakhoury, ; Geloso et al, ; Joe et al, ; Lee et al, ; Oosterhof et al, ; Ponath, Park, & Pitt, ; Zhao et al, ). In SD mice, GM2 storage is found in lysosomes of neurons, but also in lysosomes of astrocytes and microglia (Kawashima et al, ; Kyrkanides et al, ; Tsuji et al, ).…”

Section: Introductionmentioning

confidence: 99%

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Kuil

Martí

Mascaro

et al. 2019

Glia

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Sphingolipidoses are severe, mostly infantile lysosomal storage disorders (LSDs) caused by defective glycosphingolipid degradation. Two of these sphingolipidoses, Tay Sachs and Sandhoff diseases, are caused by β‐Hexosaminidase (HEXB) enzyme deficiency, resulting in ganglioside (GM2) accumulation and neuronal loss. The precise sequence of cellular events preceding, and leading to, neuropathology remains unclear, but likely involves inflammation and lysosomal accumulation of GM2 in multiple cell types. We aimed to determine the consequences of Hexb activity loss for different brain cell types using zebrafish. Hexb deficient zebrafish (hexb−/−) showed lysosomal abnormalities already early in development both in radial glia, which are the neuronal and glial progenitors, and in microglia. Additionally, at 5 days postfertilization, hexb−/− zebrafish showed reduced locomotor activity. Although specific oligosaccharides accumulate in the adult brain, hexb−/−) zebrafish are viable and apparently resistant to Hexb deficiency. In all, we identified cellular consequences of loss of Hexb enzyme activity during embryonic brain development, showing early effects on glia, which possibly underlie the behavioral aberrations. Hereby, we identified clues into the contribution of non‐neuronal lysosomal abnormalities in LSDs affecting the brain and provide a tool to further study what underlies the relative resistance to Hexb deficiency in vivo.

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Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy

Cited by 144 publications

References 34 publications

mTOR‐mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP

mTOR‐mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

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