The Role of Astrocytes in Multiple Sclerosis

Ponath, Gerald; Park, Calvin; Pitt, David

doi:10.3389/fimmu.2018.00217

Cited by 251 publications

(225 citation statements)

References 184 publications

(220 reference statements)

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“…Astrocytes play a major role in the induction and modification of brain inflammation, which is summarized and discussed in a number of excellent recent review articles (Brambilla, 2019;Ludwin, Rao, Moore, & Antel, 2016;Ponath, Park, & Pitt, 2018;Soung & Klein, 2018;Wheeler & Quintana, 2019). For this reason, only few aspects will be addressed here, which go beyond the issues covered in detail in these articles.…”

Section: Astrocytes In Experimental and Human Inflammatory Brain DImentioning

confidence: 99%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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Numerous recent studies have been performed to elucidate the function of microglia, macrophages, and astrocytes in inflammatory diseases of the central nervous system. Regarding myeloid cells a core pattern of activation has been identified, starting with the activation of resident homeostatic microglia followed by recruitment of blood borne myeloid cells. An initial state of proinflammatory activation is at later stages followed by a shift toward an‐anti‐inflammatory and repair promoting phenotype. Although this core pattern is similar between experimental models and inflammatory conditions in the human brain, there are important differences. Even in the normal human brain a preactivated microglia phenotype is evident, and there are disease specific and lesion stage specific differences in the contribution between resident and recruited myeloid cells and their lesion state specific activation profiles. Reasons for these findings reside in species related differences and in differential exposure to different environmental cues. Most importantly, however, experimental rodent studies on brain inflammation are mainly focused on autoimmune encephalomyelitis, while there is a very broad spectrum of human inflammatory diseases of the central nervous system, triggered and propagated by a variety of different immune mechanisms.

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Section: Astrocytes In Experimental and Human Inflammatory Brain DImentioning

confidence: 99%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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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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“…In animal models, as well as in resected tissues from epilepsy patients, these homeostatic mechanisms are impaired, suggesting a critical role in the pathophysiological alterations observed in epilepsy (see Coulter and Steinhauser for a detailed review). Interestingly, different polarization states of astrocytes have also been described; based on their transcriptomic profiles, these states are referred to as A1 or A2, in analogy to microglial M1 and M2 phenotypes …”

Section: Neuroinflammationmentioning

confidence: 99%

“…Interestingly, different polarization states of astrocytes have also been described; based on their transcriptomic profiles, these states are referred to as A1 or A2, in analogy to microglial M1 and M2 phenotypes. 26 Peripheral cells such as monocytes, neutrophils, and T lymphocytes can migrate to the brain and also contribute to neuroinflammation in epilepsy. 27 Migration of these cells is induced by direct injury to components of the blood-brain barrier such as pericytes and astrocytes, 28 and also by the release of proinflammatory cytokines that can compromise the blood-brain barrier.…”

Section: Key Pointsmentioning

confidence: 99%

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

et al. 2020

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Owing to the complexity of the pathophysiological mechanisms driving epileptogenesis following traumatic brain injury (TBI), effective preventive treatment approaches are not yet available for posttraumatic epilepsy (PTE). Neuroinflammation appears to play a critical role in the pathogenesis of the acquired epilepsies, including PTE, but despite a large preclinical literature demonstrating the ability of anti‐inflammatory treatments to suppress epileptogenesis and chronic seizures, no anti‐inflammatory treatment approaches have been clinically proven to date. TBI triggers robust inflammatory cascades, suggesting that they may be relevant for the pathogenesis of PTE. A major cell type involved in such cascades is the microglial cells—brain‐resident immune cells that become activated after brain injury. When activated, these cells can oscillate between different phenotypes, and such polarization states are associated with the release of various pro‐ and anti‐inflammatory mediators that may influence brain repair processes, and also differentially contribute to the development of PTE. As the molecular mechanisms and key signaling molecules associated with microglial polarization in brain are discovered, strategies are now emerging that can modulate this polarization, promoting this as a potential therapeutic strategy for PTE. In this review, we discuss the relevant literature regarding the polarization of brain‐resident immune cells following TBI and attempt to put into perspective a role in epilepsy pathogenesis. Finally, we explore potential strategies that could polarize microglia/macrophages toward a neuroprotective phenotype to mitigate PTE development.

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The Role of Astrocytes in Multiple Sclerosis

Cited by 251 publications

References 184 publications

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

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

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

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