Astrogliosis
Open accessAbstract
In addition to their many functions in the healthy central nervous system (CNS), astrocytes respond to CNS damage and disease through a process called astrogliosis. For many decades, astrogliosis was sparsely studied and enigmatic. This article examines recent evidence supporting a definition of astrogliosis as a spectrum of heterogeneous potential changes in astrocytes that occur in a context-specific manner as determined by diverse signaling events that vary with the nature and severity of different CNS insults. Astrogliosis is associated with essential beneficial functions, but under specific circumstances can lead to harmful effects. Potential dysfunctions of astrocytes and astrogliosis are being identified that can contribute to, or be primary causes of, CNS disorders, leading to the notion of astrocytopathies. A conceptual framework is presented that allows consideration of normally occurring and dysfunctional astrogliosis and their different roles in CNS disorders.
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Changes associated with reactive astrocytes in aging include upregulation of Gfap, Serpina3n, the complement cascade, and cytokines.
“The analysis of individual genes and pathways upregulated in aging astrocytes revealed changes associated with reactive astrocytes, including upregulation of Gfap, Serpina3n, the complement cascade, and cytokines (Sofroniew, 2015; Zamanian et al., 2012).”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Sofroniew, 2015
Astrocytes in the aging brain exhibit gene expression changes consistent with reactive astrocytes.
“We find that astrocytes in the aging brain exhibit gene expression changes consistent with reactive astrocytes, albeit with changes of a lesser magnitude, showing a mild to moderate level of reactivity (Sofroniew, 2015).”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Sofroniew, 2015
Astroglia interact with synapses and form part of the synapse structure.
“Astroglia are interacting with synapses and forming part of the synapse structure [86, 87]”
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Neurotoxic reactive astrocytes are induced by activated microglia
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Glial responses to implanted electrodes in the brain
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Functional diversity of astrocytes in neural circuit regulation
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Interaction of Microglia and Astrocytes in the Neurovascular Unit
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Current and Novel Polymeric Biomaterials for Neural Tissue Engineering
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Immune cell regulation of glia during CNS injury and disease
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Astrocyte Biomarkers in Alzheimer’s Disease
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Regulation of axonal regeneration after mammalian spinal cord injury
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Dopamine, Immunity, and Disease
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A1/A2 astrocytes in central nervous system injuries and diseases: Angels or devils?
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“Reactive astrocytes at the glial scar release neurotrophic and synaptogenic factors, and extracellular matrix (ECM) proteins to support neuronal survival, synapse formation, and synaptic plasticity (Sofroniew, 2009; 2015).”
Astrocyte senescence: Evidence and significance
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Questions and (some) answers on reactive astrocytes
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The role of glial-specific Kir4.1 in normal and pathological states of the CNS
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Targeting neuroinflammation in Alzheimer’s disease
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“, 2018) and since an increase in GFAP expression is a common feature of reactive/activated astrocytes (Zamanian et al., 2012; Sofroniew, 2014; Liddelow et al., 2017), these findings suggest that astrocytes become reactive with age.”
Stratification of astrocytes in healthy and diseased brain
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Glial Cells Shape Pathology and Repair After Spinal Cord Injury
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Protective Functions of Reactive Astrocytes Following Central Nervous System Insult
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Astrocytes, the rising stars of the glioblastoma microenvironment
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“…to the roles astrocytes play in the healthy CNS, they are also responsive to CNS damage and are subject to astrogliosis, a process whereby astrocytes undergo a number of molecular, cellular, and functional changes to form reactive astrocytes able to repair the affected tissue (Sofroniew, 2014).”
BackgroundTargeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders
Leitner, G. R., Wenzel, T., Marshall, N., Gates, E. J., & Klegeris, A. (2019) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2019.1676416 · Cited by 187 · see citing works
Aberrant iPSC-derived human astrocytes in Alzheimer's disease
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Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1
Lananna, B. V., Nadarajah, C. J., Izumo, M., Cedeño, M. R., Xiong, D. D., Dimitry, J. M., Tso, C. F., McKee, C. A., Griffin, P. Y., Sheehan, P. W., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.09.015 · Cited by 168 · see citing works
Neuropathobiology of COVID-19: The Role for Glia
Tremblay, M.-E., Madore, C., Bordeleau, M., Tian, L., & Verkhratsky, A. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.592214 · Cited by 159 · see citing works
“Activation of astrogliotic programme instigates changes in gene expression, in astrocytic biochemistry, morphology and physiology with an ultimate goal of protecting the CNS against pathological lesion (Sofroniew, 2014, 2015; Pekny et al., 2016; Verkhratsky et al., 2017).”
BackgroundQosa, H., Batarseh, Y. S., Mohyeldin, M. M., Sayed, K. A. E., Keller, J. N., & Kaddoumi, A. (2015) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00190 · Cited by 157 · see citing works
Roles of Regulatory T Cells in Tissue Pathophysiology and Metabolism
Campbell, C., & Rudensky, A. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.010 · Cited by 154 · see citing works
“Although astrocytes usually play a beneficial role by providing trophic support to neurons, ischemia or injury can turn these helpful “accessory cells” into neurotoxic agents (Sofroniew, 2014, Okabe and Medzhitov, 2016).”
BackgroundRen, Y., Ao, Y., O’Shea, T. M., Burda, J. E., Bernstein, A. M., Brumm, A. J., Muthusamy, N., Ghashghaei, H. T., Carmichael, S. T., Cheng, L., et al. (2017) · Scientific Reports · doi:10.1038/srep41122 · Cited by 149 · see citing works
Self-citationMechanisms of neuronal migration in the adult brain
Kaneko, N., Sawada, M., & Sawamoto, K. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14002 · Cited by 150 · see citing works
Astrocytes as Guardians of Neuronal Excitability: Mechanisms Underlying Epileptogenesis
Verhoog, Q. P., Holtman, L., Aronica, E., & van Vliet, E. A. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.591690 · Cited by 148 · see citing works
“…changes astrocytes experience during reactive astrogliosis, but over the past three decades a body of evidence has been collected that support astrogliosis heterogeneity and acknowledges a spectrum of molecular, cellular and functional changes within astrocytes upon reactive astrogliosis (32, 34).”
Luo, A., Yan, J., Tang, X., Zhao, Y., Zhou, B., & Li, S. (2019) · Inflammopharmacology · doi:10.1007/s10787-018-00559-0 · Cited by 144 · see citing works
“…responders even bystander to neuronal injury in disease, but now it is widely accepted that they carry out a variety of essential functions in the brain under healthy or pathological conditions (Ben Haim and Rowitch 2017; Dallerac and Rouach 2016; Sofroniew 2014; Sofroniew and Vinters 2010).”
BackgroundAstroglial atrophy in Alzheimer’s disease
Verkhratsky, A., Rodriguez, J. J., Pivoriūnas, A., Zorec, R., & Semyanov, A. V. (2019) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-019-02310-2 · Cited by 142 · see citing works
The Role of Cell Plasticity in Tissue Repair: Adaptive Cellular Reprogramming
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“, 2017) have been suggested to demarcate neurotoxic versus regenerative forms (Sofroniew, 2014).”
Reactive Astrogliosis: Implications in Spinal Cord Injury Progression and Therapy
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“Signal transducers STAT3, NFκB, JAK2, MAPK, SOX9, mTOR, c-JUN, Olig2, SOC3, PKA, PKC [31, 57]”
Lundin, A., Delsing, L., Clausen, M., Ricchiuto, P., Sánchez, J., Sabirsh, A., Ding, M., Synnergren, J., Zetterberg, H., Brolén, G., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.01.021 · Cited by 128 · see citing works
“The lack of conclusive and consistent human astrocyte marker profiles might reflect the complexity of various astrocytic functions (Khakh and Sofroniew, 2015), hence making it difficult to validate model representation.”
BackgroundInfluentialCholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation
Gamage, R. V., Wagnon, I. M., Rossetti, I., Childs, R., Niedermayer, G., Chesworth, R., & Gyengési, E. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.577912 · Cited by 133 · see citing works
“…has been adopted to define functional states of microglia, transcriptome analysis of microglia from animal models of neurodegeneration and aging suggests this classification is over-simplified (Chiu et al., 2013; Khakh and Sofroniew, 2015; Grabert et al., 2016; Ransohoff, 2016; Wes et al., 2016).”
BackgroundMethodGold nanostructures: synthesis, properties, and neurological applications
Zare, I., Yaraki, M. T., Speranza, G., Najafabadi, A. H., Shourangiz-Haghighi, A., Nik, A. B., Manshian, B. B., Saraiva, C., Soenen, S. J., Kogan, M. J., et al. (2022) · Chemical Society Reviews · doi:10.1039/d1cs01111a · Cited by 132 · see citing works
Fetal Alcohol Spectrum Disorders: An Overview from the Glia Perspective
Wilhelm, C., & Guizzetti, M. (2016) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2015.00065 · Cited by 128 · see citing works
“…or nothing’’ response; astrocytes are capable of a spectrum of changes (ranging from reversible alterations in gene expression and cellular hypertrophy to cell proliferation, scar formation and permanent tissue rearrangement) tailored to the type of insult they are responding to Sofroniew (2014).”
BackgroundLiu, C.-Y., Yang, Y., Ju, W.-N., Wang, X., & Zhang, H.-L. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00193 · Cited by 131 · see citing works
“…3 (STAT3), NF-κB, cAMP, Rho-kinase, JNK, Olig2, CEPB1 and EphB2 are involved in mediating different aspects or different degrees of astrogliosis, including cell hypertrophy, proliferation, migration and scar formation as well as up-regulation of GFAP, vimentin and nestin (Sofroniew, 2014).”
BackgroundA neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models
Tyzack, G. E., Hall, C. E., Sibley, C. R., Cymes, T., Forostyak, S., Carlino, G., Meyer, I. F., Schiavo, G., Zhang, S.-C., Gibbons, G. M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01283-z · Cited by 128 · see citing works
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Astroglia in Sepsis Associated Encephalopathy
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Astrocytogenesis: where, when, and how
Akdemir, E. S., Huang, A. Y.-S., & Deneen, B. (2020) · F1000Research · doi:10.12688/f1000research.22405.1 · Cited by 115 · see citing works
The contribution of glial cells to Huntington's disease pathogenesis
Wilton, D. K., & Stevens, B. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104963 · Cited by 112 · see citing works
“…a reactive state at both later stages of disease progression in HD mouse models and following conditional deletion of the WT huntingtin protein, is also seen in post-mortem tissue from HD patients (Faideau et al., 2010; Gu et al., 2015; McKinstry et al., 2014; Sofroniew, 2014; Tong et al., 2014).”
BackgroundAstrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders
Satarker, S., Bojja, S. L., Gurram, P. C., Mudgal, J., Arora, D. S., & Nampoothiri, M. (2022) · Cells · doi:10.3390/cells11071139 · Cited by 112 · see citing works
Multiple sclerosis: New insights and trends
Koriem, K. M. M. (2016) · Asian Pacific Journal of Tropical Biomedicine · doi:10.1016/j.apjtb.2016.03.009 · Cited by 112 · see citing works
High resolution dissection of reactive glial nets in Alzheimer’s disease
Bouvier, D. S., Jones, E. V., Quesseveur, G., Davoli, M. A., A. Ferreira, T., Quirion, R., Mechawar, N., & Murai, K. K. (2016) · Scientific Reports · doi:10.1038/srep24544 · Cited by 111 · see citing works
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Metabolic changes favor the activity and heterogeneity of reactive astrocytes
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Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration after Spinal Cord Injury
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Astroglial Calcium Signaling in Aging and Alzheimer's Disease
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“…reactivity produces multiple pathological phenotypes, which are context- and disease-specific, and may exert either neuroprotective or neurotoxic effects (Zamanian et al. 2012; Burda and Sofroniew 2014; Pekny and Pekna 2014; Sofroniew 2014a,b, 2015; Pekny et al. 2016; Liddelow andBarres 2017).”
BackgroundMolecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD
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“This data supports previous observations (Wil-helmsson et al. 2006; Sofroniew 2015).”
BackgroundResultInfluentialNeuroinflammation Is Associated with GFAP and sTREM2 Levels in Multiple Sclerosis
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“Astrocyte proliferation occurs after sustained exposure to damage, whether in the presence of a chronic neurodegenerative process, trauma, ischemic and infectious processes (Sofroniew, 2014).”
Mesenchymal stromal cells (MSCs) for neurodegenerative disease: A promising frontier
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“…was long viewed as homogenous and functionally passive, consisting of a stereotyped set of changes driving the conversion of homeostatic astrocytes to a distinct phenotype—the “reactive astrocyte” (Eddleston and Mucke, 1993; Anderson et al., 2014; Pekny and Pekna, 2014; Sofroniew, 2015).”
InfluentialAstrocyte-Mediated Neuroinflammation in Neurological Conditions
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“Notably, such BBB breakage directly results in the infiltration of peripheral immune cells from the blood circulation.”
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Emerging evidence for astrocyte dysfunction in schizophrenia
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“Astroglial pathological modifications are driven by different signaling mechanisms and produce diverse responses from adaptive to maladaptive, and further they may change along the course of a disease (Sofroniew, 2014; Pekny et al., 2016; Verkhratsky et al., 2017).”
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Understanding exosomes: Part 2—Emerging leaders in regenerative medicine
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“12 Initially, reactive astrogliosis is a protective process involving multiple cellular and molecular responses to CNS injury.”
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“However, others have shown that astrogliosis may be harmful, as in the context of inflammation (Sofroniew 2015; Sofroniew and Vinters 2010).”
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“In addition, these cells importantly contribute to synaptogenesis and dynamically modulate information processing and signal transmission, regulate neural and synaptic plasticity, and provide trophic and metabolic support to neurons (Perea et al., 2009; Sofroniew, 2014).”
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Redox Signaling, Neuroinflammation, and Neurodegeneration
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“Oneormoreoftheprocessesmentionedearlierderiveina response that is known formally as reactive gliosis (88, 225), a state that exhibits a complex nature and holds the potential to interrelate by many molecular signaling mechanisms (22, 226).”
- Authors
- Sofroniew, M. V.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Sofroniew, Michael V.
- Venue
- Cold Spring Harbor Perspectives in Biology
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2014-11-07
- Volume
- 7
- Issue
- 2
- Pages
- a020420
- ISSN
- 1943-0264 (ISSN-L)
- PMC
- PMC4315924
- OpenAlex
- W4239346618
- Cited by
- 695
- References
- 109
- Citations by year
- 2026: 44 · 2025: 53 · 2024: 84 · 2023: 83 · 2022: 101 · 2021: 83 · 2020: 86 · 2019: 61 · 2018: 38 · 2017: 27 · 2016: 21 · 2015: 13 · 2014: 1
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- astrocyte activation, astrocytes, astrocytopathy, central nervous system injury, central nervous system disorders, astrocyte dysfunction
- MeSH terms
- Astrocytes, Cell Communication, Cell Movement, Central Nervous System, Central Nervous System Diseases, Cicatrix, Models, Biological, Mutation, Signal Transduction
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