The dual role of astrocyte activation and reactive gliosis

doi:10.1016/j.neulet.2013.12.071

Neuroscience Letters

Volume 565, 17 April 2014, Pages 30-38

https://doi.org/10.1016/j.neulet.2013.12.071 Get rights and content

Highlights

•
Astrocyte activation (AA) and reactive gliosis (RG) accompany many CNS pathologies.
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AA and RG alter the expression of many genes and astrocyte function.
•
RG benefits include lesion sequestering, neuroprotection, and counteracting acute stress.
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If not resolved on time, AA and RG inhibit neuroplasticity and CNS regeneration.
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AA and RG is an important therapeutic target.

Abstract

Astrocyte activation and reactive gliosis accompany most of the pathologies in the brain, spinal cord, and retina. Reactive gliosis has been described as constitutive, graded, multi-stage, and evolutionary conserved defensive astroglial reaction [Verkhratsky and Butt (2013) In: Glial Physiology and Pathophysiology]. A well- known feature of astrocyte activation and reactive gliosis are the increased production of intermediate filament proteins (also known as nanofilament proteins) and remodeling of the intermediate filament system of astrocytes. Activation of astrocytes is associated with changes in the expression of many genes and characteristic morphological hallmarks, and has important functional consequences in situations such as stroke, trauma, epilepsy, Alzheimer's disease (AD), and other neurodegenerative diseases. The impact of astrocyte activation and reactive gliosis on the pathogenesis of different neurological disorders is not yet fully understood but the available experimental evidence points to many beneficial aspects of astrocyte activation and reactive gliosis that range from isolation and sequestration of the affected region of the central nervous system (CNS) from the neighboring tissue that limits the lesion size to active neuroprotection and regulation of the CNS homeostasis in times of acute ischemic, osmotic, or other kinds of stress. The available experimental data from selected CNS pathologies suggest that if not resolved in time, reactive gliosis can exert inhibitory effects on several aspects of neuroplasticity and CNS regeneration and thus might become a target for future therapeutic interventions.

Section snippets

Experimental models to understand injury- or ischemia-triggered astrocyte activation and reactive gliosis

Over the past two decades, several animal models have been used in a series of experimental studies to understand the role of astrocyte activation and reactive gliosis in neurological diseases as well as neuroplasticity and regeneration processes.

What are the consequences of the elimination of astrocytes, elimination of reactive astrocytes or inhibition/attenuation of astrocyte activation? Elimination of astrocytes in a mammal is lethal [43]. The demarcation of CNS lesion by reactive astrocytes

Experimental modulation of astrocyte activation and reactive gliosis in chronic neurodegeneration

Reactive astrocytes are a prominent histopathological feature of many neurodegenerative diseases including AD, where they surround and closely associate with amyloid plaques. In the past, astrocyte activation and reactive gliosis in AD and other neurodegenerative disorders was viewed as part of the neuroinflammatory neurotoxic response [83], [84]. On the other hand, adult astrocytes in brain slices from an AD mouse model were shown to migrate and degrade amyloid plaques [85] in an

Reactive astrocytes and activated microglia–an important crosstalk in neurodegeneration?

Remarkably, there appears to be a bidirectional relationship between the activation of astrocytes and activation/recruitment of microglia and monocytes, at least in the context of neurodegeneration. The ablation of GFAP and vimentin led to attenuated CD11b-positive microglia/monocyte infiltration after retinal detachment, suggesting a key role for reactive retinal glial cells in recruiting microglia/monocytes to the injured areas, conceivably through the production of chemokines such as

Does gender matter?

Given the sex differences in the morphology and function of astrocytes at least in some regions of the developing and adult brain [99], [100], it is perhaps not surprising that male and female astrocytes show different sensitivity to hypoxia [101], and may respond differentially to an inflammatory challenge. Despite similar basal expression of IL-6, TNF-alpha, IL-1beta, and the LPS receptor (Toll-like receptor 4), the mRNA levels of IL-6, TNF-alpha, and IL-1beta were manifold higher in LPS

Astrocytes and synapse elimination

TGF-beta secreted by immature astrocytes in the retina has been recently shown to initiate synaptic elimination in the postnatal thalamus by regulating the expression of C1q in the retinal ganglion cells [104]. C1q is a complement protein that triggers the activation of the classical complement pathway which leads to the tagging of the supernumerary synapses with complement-activation derived C3b fragment and their subsequent elimination by microglia [105], [106]. C1q upregulation in microglia

Are there any downsides of astrocyte activation and reactive gliosis?

There is a growing body of evidence pointing to negative consequences of reactive gliosis in particular when it does not get resolved within the post-acute and the early chronic stage after injury. Reactive gliosis and glial scarring have inhibitory effects on CNS regeneration as shown in a number of experimental models with the whole range of molecules implicated in this process [110], [111], [112], [113], [114]. Post-traumatic axonal regeneration can be improved by inhibition of chondroitin

Astrocytes and reactive astrocytes as a therapeutic target

Importantly, the available data make it paramount to recognize both the beneficial and detrimental side of reactive gliosis asking for high caution, not least when it comes to the timing of its therapeutic modulation. For example, attenuation of reactive gliosis after partial hippocampal de-afferentation induced by entorhinal cortex lesions [130], [131] in GFAP^−/−Vim^−/− mice resulted in better regeneration of neuronal synapses in the post-acute phase; however, the synaptic loss and signs of

Acknowledgments

This work was supported by Swedish Medical Research Council (11548 to MPy, 20116 to MPa), ALF Gothenburg (11267 to MPa and 146051 to MPy), AFA Research Foundation, Söderbergs Foundations, Sten A. Olsson Foundation for Research and Culture, Hjärnfonden, Hagströmer's Foundation Millennium, Amlöv's Foundation, E. Jacobson's Donation Fund, VINNOVA, the Swedish Stroke Foundation, NanoNet COST Action (BM1002), EU FP 7 Program EduGlia (237956), and EU FP 7 Program TargetBraIn (279017).

References (160)

K.S. Christopherson et al.
Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis
Cell
(2005)
H.B. Choi et al.
Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase
Neuron
(2012)
M. Simard et al.
The neurobiology of glia in the context of water and ion homeostasis
Neuroscience
(2004)
A. Suzuki et al.
Astrocyte-neuron lactate transport is required for long-term memory formation
Cell
(2011)
B.A. Barres
The mystery and magic of glia: a perspective on their roles in health and disease
Neuron
(2008)
E.A. Bushong et al.
Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development
Int. J. Dev. Neurosci.
(2004)
V. Matyash et al.
Heterogeneity in astrocyte morphology and physiology
Brain Res. Rev.
(2010)
Y. Zhang et al.
Astrocyte heterogeneity: an underappreciated topic in neurobiology
Curr. Opin. Neurobiol.
(2010)
R. Beckervordersandforth et al.
In vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells
Cell Stem Cell
(2010)
K. Sriram et al.
Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo?
J. Biol. Chem.
(2004)

M. Eddleston et al.

Molecular profile of reactive astrocytes–implications for their role in neurologic disease

Neuroscience

(1993)

M.V. Sofroniew

Molecular dissection of reactive astrogliosis and glial scar formation

Trends Neurosci.

(2009)

B.J. Kerr et al.

Potent pro-inflammatory actions of leukemia inhibitory factor in the spinal cord of the adult mouse

Exp. Neurol.

(2004)

X.G. Xia et al.

Induction of STAT3 signaling in activated astrocytes and sprouting septal neurons following entorhinal cortex lesion in adult rats

Mol. Cell. Neurosci.

(2002)

F. Renault-Mihara et al.

Spinal cord injury: emerging beneficial role of reactive astrocytes’ migration

Int. J. Biochem. Cell. Biol.

(2008)

T.G. Bush et al.

Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice

Neuron

(1999)

M.V. Sofroniew et al.

Genetically-targeted and conditionally-regulated ablation of astroglial cells in the central, enteric and peripheral nervous systems in adult transgenic mice

Brain Res.

(1999)

C. Eliasson et al.

Intermediate filament protein partnership in astrocytes

J. Biol. Chem.

(1999)

M. Pekny et al.

Intermediate filaments and stress

Exp. Cell Res.

(2007)

K. Dietzmann et al.

Expression of the plasminogen activator system and the inhibitors PAI-1 and PAI-2 in posttraumatic lesions of the CNS and brain injuries following dramatic circulatory arrests: an immunohistochemical study

Pathol. Res. Pract.

(2000)

M. Ding et al.

Altered taurine release following hypotonic stress in astrocytes from mice deficient for GFAP and vimentin

Brain Res. Mol. Brain Res.

(1998)

R.E. Mrak et al.

Glial cytokines in Alzheimer's disease: review and pathogenic implications

Hum. Pathol.

(1995)

S. Askarova et al.

Role of Abeta-receptor for advanced glycation endproducts interaction in oxidative stress and cytosolic phospholipase A(2) activation in astrocytes and cerebral endothelial cells

Neuroscience

(2011)

S.L. Hofmann et al.

Infantile neuronal ceroid lipofuscinosis: no longer just a ‘Finnish’ disease

Eur. J. Paediatr. Neurol.

(2001)

S.L. Hofmann et al.

Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency

Mol. Genet. Metab.

(1999)

C. Kielar et al.

Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis

Neurobiol. Dis.

(2007)

S.L. Macauley et al.

Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse

Exp. Neurol.

(2009)

J.M. Schwarz et al.

Sex, glia, and development: interactions in health and disease

Horm. Behav.

(2012)

E.M. Ullian et al.

Control of synapse number by glia

Science

(2001)

E.M. Ullian et al.

Role for glia in synaptogenesis

Glia

(2004)

C. Eroglu et al.

Regulation of synaptic connectivity by glia

Nature

(2010)

L. Pellerin et al.

Activity-dependent regulation of energy metabolism by astrocytes: an update

Glia

(2007)

N. Rouach et al.

Astroglial metabolic networks sustain hippocampal synaptic transmission

Science

(2008)

S. Liebner et al.

Current concepts of blood-brain barrier development

Int. J. Dev. Biol.

(2011)

D. Attwell et al.

Glial and neuronal control of brain blood flow

Nature

(2010)

S.J. Mulligan et al.

Calcium transients in astrocyte endfeet cause cerebrovascular constrictions

Nature

(2004)

M. Zonta et al.

Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation

Nat. Neurosci.

(2003)

T. Kosaka et al.

Three-dimensional structure of astrocytes in the rat dentate gyrus

J. Comp. Neurol.

(1986)

J. Grosche et al.

Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells

Nat. Neurosci.

(1999)

E.A. Bushong et al.

Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains

J. Neurosci.

(2002)

M. Haber et al.

Reshaping neuron-glial communication at hippocampal synapses

Neuron Glia. Biol.

(2006)

N.A. Oberheim et al.

Uniquely hominid features of adult human astrocytes

J. Neurosci.

(2009)

S. Bardehle et al.

Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation

Nat. Neurosci.

(2013)

A. Stahlberg et al.

Defining cell populations with single-cell gene expression profiling: correlations and identification of astrocyte subpopulations

Nucleic Acids Res.

(2011)

J.L. Zamanian et al.

Genomic analysis of reactive astrogliosis

J. Neurosci.

(2012)

V. Balasingam et al.

Reactive astrogliosis in the neonatal mouse brain and its modulation by cytokines

J. Neurosci.

(1994)

M.A. Klein et al.

Impaired neuroglial activation in interleukin-6 deficient mice

Glia

(1997)

A.G. Rabchevsky et al.

A role for transforming growth factor alpha as an inducer of astrogliosis

J. Neurosci.

(1998)

C.G. Winter et al.

A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury

Proc. Natl. Acad. Sci. USA

(1995)

L.F. Eng et al.

GFAP and astrogliosis

Brain Pathol.

(1994)

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Mini-reviewThe dual role of astrocyte activation and reactive gliosis

Highlights

Abstract

Section snippets

Experimental models to understand injury- or ischemia-triggered astrocyte activation and reactive gliosis

Experimental modulation of astrocyte activation and reactive gliosis in chronic neurodegeneration

Reactive astrocytes and activated microglia–an important crosstalk in neurodegeneration?

Does gender matter?

Astrocytes and synapse elimination

Are there any downsides of astrocyte activation and reactive gliosis?

Astrocytes and reactive astrocytes as a therapeutic target

Acknowledgments

Cell

Neuron

Neuroscience

Cell

Neuron

Int. J. Dev. Neurosci.

Brain Res. Rev.

Curr. Opin. Neurobiol.

Cell Stem Cell

J. Biol. Chem.

Neuroscience

Trends Neurosci.

Exp. Neurol.

Mol. Cell. Neurosci.

Int. J. Biochem. Cell. Biol.

Neuron

Brain Res.

J. Biol. Chem.

Exp. Cell Res.

Pathol. Res. Pract.

Brain Res. Mol. Brain Res.

Hum. Pathol.

Neuroscience

Eur. J. Paediatr. Neurol.

Mol. Genet. Metab.

Neurobiol. Dis.

Exp. Neurol.

Horm. Behav.

Control of synapse number by glia

Science

Role for glia in synaptogenesis

Glia

Regulation of synaptic connectivity by glia

Nature

Activity-dependent regulation of energy metabolism by astrocytes: an update

Glia

Astroglial metabolic networks sustain hippocampal synaptic transmission

Science

Current concepts of blood-brain barrier development

Int. J. Dev. Biol.

Glial and neuronal control of brain blood flow

Nature

Calcium transients in astrocyte endfeet cause cerebrovascular constrictions

Nature

Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation

Nat. Neurosci.

Three-dimensional structure of astrocytes in the rat dentate gyrus

J. Comp. Neurol.

Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells

Nat. Neurosci.

Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains

J. Neurosci.

Reshaping neuron-glial communication at hippocampal synapses

Neuron Glia. Biol.

Uniquely hominid features of adult human astrocytes

J. Neurosci.

Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation

Nat. Neurosci.

Defining cell populations with single-cell gene expression profiling: correlations and identification of astrocyte subpopulations

Nucleic Acids Res.

Genomic analysis of reactive astrogliosis

J. Neurosci.

Reactive astrogliosis in the neonatal mouse brain and its modulation by cytokines

J. Neurosci.

Impaired neuroglial activation in interleukin-6 deficient mice

Glia

A role for transforming growth factor alpha as an inducer of astrogliosis

J. Neurosci.

Mini-review
The dual role of astrocyte activation and reactive gliosis