The Role of Astrocytes in CNS Inflammation

Giovannoni, Federico; Quintana, Francisco J.

doi:10.1016/j.it.2020.07.007

Cited by 387 publications

(276 citation statements)

References 132 publications

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“…By comparing healthy enriched cluster 1 and early disease enriched cluster 2 within each dataset, we identified a shared gene signature enriched in the early pathology subcluster across all three diseases. The integrated gene signature included markers of activated astrocytes, including VIM, GFAP, CRYAB, and CD81 [38,39], major histocompatibility complex (MHC) class I (B2M ) [40,41], iron metabolism (FTH1 and FTL), a water channel component implicated in debris clearance (AQP4 ) [42], along with lysosomal activation and lipid and amyloid phagocytosis (CTSB, APOE ). Of interest, many upregulated genes were shared between the microglial and astrocyte early activation signatures, suggesting common glial stress pathways may become activated in response to neurodegeneration.…”

Section: Resultsmentioning

confidence: 99%

Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases

Kuchroo

DiStasio

Calapkulu

et al. 2021

Preprint

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1One Sentence SummaryA novel topological machine learning approach applied to single-nucleus RNA sequencing from human retinas with age-related macular degeneration identifies interacting disease phase-specific glial activation states shared with Alzheimer’s disease and multiple sclerosis.2AbstractNeurodegeneration occurs in a wide range of diseases, including age-related macular degeneration (AMD), Alzheimer’s disease (AD), and multiple sclerosis (MS), each with distinct inciting events. To determine whether glial transcriptional states are shared across phases of degeneration, we sequenced 50,498 nuclei from the retinas of seven AMD patients and six healthy controls, generating the first single-cell transcriptomic atlas of AMD. We identified groupings of cells implicated in disease pathogenesis by applying a novel topologically-inspired machine learning approach called ‘diffusion condensation.’ By calculating diffusion homology features and performing persistence analysis, diffusion condensation identified activated glial states enriched in the early phases of AMD, AD, and MS as well as an AMD-specific proangiogenic astrocyte state promoting pathogenic neovascularization in advanced AMD. Finally, by mapping the expression of disease-associated genes to glial states, we identified key signaling interactions creating hypotheses for therapeutic intervention. Our topological analysis identified an integrated disease-phase specific glial landscape that is shared across neurodegenerative conditions affecting the central nervous system.

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Section: Resultsmentioning

confidence: 99%

Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases

Kuchroo

DiStasio

Calapkulu

et al. 2021

Preprint

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“…In turn, they can release a variety of biomolecules, which can selectively target neurons, thus contributing to their maturation and survival, and to the modulation of synaptic function (Durkee and Araque, 2019). Astrocytes also react to pro-inflammatory molecules released from other CNS cells and are able to mediate inflammatory responses (Giovannoni and Quintana, 2020), highlighting the diversity of processes in which astrocytes are involved.…”

Section: Role Of Astrocyte-derived Evs In the Central Nervous Systemmentioning

confidence: 99%

Glia-Derived Extracellular Vesicles: Role in Central Nervous System Communication in Health and Disease

Pistono

Bister

Stanová

et al. 2021

Front. Cell Dev. Biol.

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Glial cells are crucial for the maintenance of correct neuronal functionality in a physiological state and intervene to restore the equilibrium when environmental or pathological conditions challenge central nervous system homeostasis. The communication between glial cells and neurons is essential and extracellular vesicles (EVs) take part in this function by transporting a plethora of molecules with the capacity to influence the function of the recipient cells. EVs, including exosomes and microvesicles, are a heterogeneous group of biogenetically distinct double membrane-enclosed vesicles. Once released from the cell, these two types of vesicles are difficult to discern, thus we will call them with the general term of EVs. This review is focused on the EVs secreted by astrocytes, oligodendrocytes and microglia, aiming to shed light on their influence on neurons and on the overall homeostasis of the central nervous system functions. We collect evidence on neuroprotective and homeostatic effects of glial EVs, including neuronal plasticity. On the other hand, current knowledge of the detrimental effects of the EVs in pathological conditions is addressed. Finally, we propose directions for future studies and we evaluate the potential of EVs as a therapeutic treatment for neurological disorders.

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“…However, it is now apparent that these are not the most informative markers to evaluate the outcome of astrocyte reactivity, since their upregulation does not distinguish between different types of reactivity (Liddelow et al, 2017). Nuclear factor‐κB (NFκB) activation is one of the early indicators and regulators of neurotoxic‐astrocyte reactivity (Giovannoni & Quintana, 2020; Liddelow & Barres, 2017), yet the increase in NFκB transcription is transient (Liu, Zhang, Joo, & Sun, 2017). Fortunately, transcriptomic studies identified transcripts that are specifically upregulated in neuroinflammatory/neurotoxic astrocytes, such as complement component C3 (Liddelow et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Novel factor in olfactory ensheathing cell‐astrocyte crosstalk: Anti‐inflammatory protein α‐crystallin B

Saglam

Calof

Wray

2020

Glia

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Astrocytes are key players in CNS neuroinflammation and neuroregeneration that may help or hinder recovery, depending on the context of the injury. Although pro‐inflammatory factors that promote astrocyte‐mediated neurotoxicity have been shown to be secreted by reactive microglia, anti‐inflammatory factors that suppress astrocyte activation are not well‐characterized. Olfactory ensheathing cells (OECs), glial cells that wrap axons of olfactory sensory neurons, have been shown to moderate astrocyte reactivity, creating an environment conducive to regeneration. Similarly, astrocytes cultured in medium conditioned by cultured OECs (OEC‐CM) show reduced nuclear translocation of nuclear factor kappa‐B (NFκB), a pro‐inflammatory protein that induces neurotoxic reactivity in astrocytes. In this study, we screened primary and immortalized OEC lines to identify these factors and discovered that Alpha B‐crystallin (CryAB), an anti‐inflammatory protein, is secreted by OECs via exosomes, coordinating an intercellular immune response. Our results showed that: (a) OEC exosomes block nuclear NFκB translocation in astrocytes while exosomes from CryAB‐null OECs could not; (b) OEC exosomes could be taken up by astrocytes, and (c) CryAB treatment suppressed neurotoxicity‐associated astrocyte transcripts. Our results indicate CryAB, as well as other factors secreted by OECs, are potential agents that can ameliorate, or even reverse, the growth‐inhibitory environment created by neurotoxic reactive astrocytes following CNS injuries.

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The Role of Astrocytes in CNS Inflammation

Cited by 387 publications

References 132 publications

Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases

Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases

Glia-Derived Extracellular Vesicles: Role in Central Nervous System Communication in Health and Disease

Novel factor in olfactory ensheathing cell‐astrocyte crosstalk: Anti‐inflammatory protein α‐crystallin B

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