Genomic analysis of reactive astrogliosis
Open accessAbstract
Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries and diseases. To better understand the reactive astrocyte state, we used Affymetrix GeneChip arrays to profile gene expression in populations of reactive astrocytes isolated at various time points after induction using two mouse injury models, ischemic stroke and neuroinflammation. We find reactive gliosis consists of a rapid, but quickly attenuated, induction of gene expression after insult and identify induced Lcn2 and Serpina3n as strong markers of reactive astrocytes. Strikingly, reactive astrocyte phenotype strongly depended on the type of inducing injury. Although there is a core set of genes that is upregulated in reactive astrocytes from both injury models, at least 50% of the altered gene expression is specific to a given injury type. Reactive astrocytes in ischemia exhibited a molecular phenotype that suggests that they may be beneficial or protective, whereas reactive astrocytes induced by LPS exhibited a phenotype that suggests that they may be detrimental. These findings demonstrate that, despite well established commonalities, astrocyte reactive gliosis is a highly heterogeneous state in which astrocyte activities are altered to respond to the specific injury. This raises the question of how many subtypes of reactive astrocytes exist. Our findings provide transcriptome databases for two subtypes of reactive astrocytes that will be highly useful in generating new and testable hypotheses of their function, as well as for providing new markers to detect different types of reactive astrocytes in human neurological diseases.
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Neuroinflammation and ischemia induced two different types of reactive astrocytes termed A1 and A2.
“We previously purified and gene profiled reactive astrocytes from mice treated either with a systemic injection of lipopolysaccharide (LPS), or received middle cerebral artery occlusion to induce ischemia5. We found neuroinflammation and ischemia induced two different types of reactive astrocytes that we termed “A1” and “A2” respectively”
From Neurotoxic reactive astrocytes are induced by activated microglia (2017) · cites this paper as [5]
The Discussion section on stimulus-dependent phenotypes reports distinct LPS- and MCAO-induced reactive astrocyte subtypes, supporting the core finding. Our copy calls them the LPS and MCAO subtypes, but does not show that this paper termed them “A1” and “A2”; searches for those labels returned no matching passage. Page numbers were unavailable. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe neuroprotective phenotype of astrocytes promotes neuronal survival and homeostasis, as these astrocytes secrete neurotrophic factors and anti-inflammatory cytokines.
“Conversely, the “neuroprotective” phenotype of astrocytes promotes neuronal survival and homeostasis, as these astrocytes secrete neurotrophic factors and anti-inflammatory cytokines [184, 187, 188].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [187]
The Discussion (page not provided) suggests that MCAO-reactive astrocytes have a protective orientation and reports high expression of neurotrophic factors and cytokines. It does not establish that these factors are secreted, identify the cytokines as anti-inflammatory, or demonstrate that this mechanism promotes neuronal survival and homeostasis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn response to injury or disease, astrocytes commonly mount a neuroinflammatory response, which induces a reactive cellular state.
“In response to injury or disease, astrocytes commonly mount a neuroinflammatory response, which then induces a reactive cellular state (Sofroniew and Vinters, 2010; Zamanian et al., 2012).”
From Sterol dysregulation in Smith–Lemli–Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk (2022) · cites this paper as Zamanian et al., 2012
The Introduction says reactive astrogliosis is a response to brain injury and disease. The Discussion section on inducing stimuli describes immune-system signals as one possible trigger and says reactive astrocytes interact with immune cells; it does not establish that astrocytes first mount a neuroinflammatory response that then induces their reactive state. (LLM, conf=0.86)
Experimental — accuracy not yet measuredWild-type littermate controls had a normal response to LPS injection with robust induction of an A1 response.
“As expected, wild-type littermate controls had a normal response to LPS injection5,17, with robust induction of an A1 response (Fig. 1a)”
From Neurotoxic reactive astrocytes are induced by activated microglia (2017) · cites this paper as [5]
Reactive astrocytes are diverse, as demonstrated by transcriptomic profiling of mouse bulk astrocytes or preselected astrocyte populations.
“Likewise, reactive astrocytes are also diverse, as unequivocally demonstrated by microarray-based66–68 and RNAseq-based48,69–71 transcriptomic profiling of mouse bulk astrocytes48,66–70 or of astrocyte populations preselected according to cell-surface markers71.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [66]
Transcriptomic profiling shows that reactive astrocytes adopt distinct molecular states in different disease models, in different CNS regions, and in brain tumors.
“Such transcriptomic profiling specifically shows that reactive astrocytes adopt distinct molecular states in different disease models48,66–70, in different CNS regions70, and in brain tumors71.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [66]
Astrocyte clusters were scored using AddModuleScore for markers from previously published genesets of astrocyte cell states, plaque-induced genes, and AD risk genes.
“Astrocyte clusters were scored using seurat::AddModuleScore(), for markers from previously published genesets of astrocyte cell states (Zamanian et al, 2012; Hasel et al, 2021), plaque-induced genes (PIGs) (Chen et al, 2020) and AD risk genes (Bellenguez et al, 2022).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Zamanian et al, 2012
Transcriptomic studies suggested complex functional changes in reactive astrocytes, including novel regenerative functions, proliferation, neural stem cell potential, and loss of homeostatic functions.
“These studies also suggested complex functional changes in reactive astrocytes, including novel regenerative functions70, proliferation, and neural stem cell potential68, as well as loss of homeostatic functions66.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [66]
Citation 66 is attached to the claim that reactive astrocytes lose homeostatic functions. The Discussion describes extensive gene-expression changes and identifies transporters and channels involved in homeostasis, but does not say that homeostatic functions are lost. Searches for loss of homeostatic function and down-regulation of homeostatic genes found no passage establishing that point. (LLM, conf=0.73)
Experimental — accuracy not yet measuredThere are 7 core aging-upregulated genes overlapping all brain regions, including Gfap, Serpina3n, and C4b.
“To identify core aging-upregulated genes, we looked for overlap in gene expression changes between all brain regions and identified 7 genes (Figure 2D), including markers of reactive as-trocytes, Gfap and Serpina3n (Zamanian et al., 2012), and a component of the complement cascade involved in synapse elimination, C4b (Sekar et al., 2016).”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Zamanian et al., 2012
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 Zamanian et al., 2012
The PIGs module has strong associations with activated microglia (DAM/ARM, odds ratio: 3.71) and inflammatory astrocytes (A1, odds ratio: 3.84).
“We investigated the cellular signatures of the PIGs module, and identified strong associations with activated microglia (DAM/ARM, odds ratio: 3.71) (Keren-Shaul et al. , 2017; Sala Frigerio et al. , 2019) and inflammatory astrocytes (A1, odds ratio: 3.84) (Zamanian et al. , 2012) (Figure S3D).”
From Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease (2020) · cites this paper as Zamanian et al., 2012
A1 astrocytes strongly upregulate genes involved in classical complement activation such as C4.
“The release of C1q from microglia is necessary to induce neurotoxic, inflammatory astrocytes (A1) (Liddelow et al. , 2017), which also strongly upregulate genes involved in classical complement activation such as C4 (Figure 4I and S4B) (Zamanian et al. , 2012).”
From Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease (2020) · cites this paper as Zamanian et al., 2012
A1 astrocytes show strongly induced expression of complement proteins C1r, C1s, C3, and C4.
“Notably, A1 astrocytes show strongly induced expression of complement proteins C1r, C1s, C3, and C4 (Zamanian et al., 2012).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Zamanian et al., 2012
A1 astrocytes are upregulated in AD and other neurodegenerative disorders.
“Importantly, this group has demonstrated that A1 astrocytes are upregulated in AD and other neurodegenerative disorders, though additional tauopathies were not tested.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [123]
A1 astrocytes lost their ability to promote neuronal survival, growth, synaptogenesis, and phagocytosis and were highly toxic to neurons.
“A1 astrocytes lost their ability to promote neuronal survival, growth, synaptogenesis, and phagocytosis and were also highly toxic to neurons, though the exact mechanism of toxicity is still unknown [122, 123].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [123]
Activated microglia induce an 'A1' astrocytic subtype by secretion of IL-1α, TNF, and C1q.
“These studies illustrated activated microglia induce what was termed an “A1” astrocytic subtype by secretion of IL-1α, TNF, and C1q.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [123]
Astrocyte markers were more mixed in M4, with a majority shared between deleterious A1 and protective A2 phenotypes.
“Astrocyte markers were more mixed in module M4, with a majority of markers being shared between deleterious A1 and protective A2 phenotypes26.”
TF network analysis identified eleven TFs upregulated in PS19 mice implicated in inflammatory responses (Stat1, Stat3, Stat5a, Stat5b, Nfkb1, Nfe2l2, Fli1), microglia proliferation/differentiation (Irf8, Spi1, Runx1), and astrocyte maturation/neurogenesis (Pax6).
“We identified eleven TFs upregulated in PS19 mice that are implicated in mediating the inflammatory responses (Stat1, Stat3, Stat5a, Stat5b, Nfkb1, Nfe2l2, Fli1), microglia proliferation and differentiation (Irf8, Spi1, Runx1), and astrocyte maturation and neurogenesis (Pax6) (Ginhoux et al., 2010; Kierdorf et al., 2013; Zamanian et al., 2012; Zusso et al., 2012).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Zamanian et al., 2012
Two distinct populations of reactive astrocytes induced by inflammation or ischemia have been identified, termed A1 astrocytes and A2 astrocytes.
“A recent study identified two distinct populations of reactive astrocytes induced by inflammation or ischemia, termed as A1 astrocytes and A2 astrocytes, respectively77.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [77]
A1 astrocytes strongly upregulate genes involved in classical complement activation which are shown to be destructive to synapses, therefore are considered harmful; whereas A2 astrocytes upregulate neurotrophic genes that promote neuronal survival and growth, and are deemed protective.
“A1 astrocytes strongly upregulate genes involved in classical complement activation which are shown to be destructive to synapses, therefore are considered harmful; whereas A2 astrocytes upregulate neurotrophic genes that promote neuronal survival and growth, and are deemed protective77.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [77]
Genes upregulated in different injury paradigms were differentially enriched in distinct astrocyte subclusters with the highest enrichment in ependymal cells.
“In addition, genes upregulated in different injury paradigms were differentially enriched in distinct astrocyte subclusters with the highest enrichment in ependymal cells (Figure S2D; Llorens-Bobadilla et al., 2015; Zamanian et al., 2012).”
From Single-Cell Analysis of Regional Differences in Adult V-SVZ Neural Stem Cell Lineages (2019) · cites this paper as Zamanian et al., 2012
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- Authors
- Zamanian, J. L., Xu, L., Foo, L. C., Nouri, N., Zhou, L., Giffard, R. G., & Barres, B. A.
- Affiliations
- Stanford Medicine (US)
- Northwestern University (US)
- Corresponding author
- Zamanian, Jennifer L.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-05-02
- Volume
- 32
- Issue
- 18
- Pages
- 6391-6410
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3480225
- OpenAlex
- W2084566588
- Cited by
- 2,404
- References
- 73
- Citations by year
- 2026: 122 · 2025: 184 · 2024: 245 · 2023: 269 · 2022: 287 · 2021: 268 · 2020: 226 · 2019: 195 · 2018: 143 · 2017: 107 · 2016: 98 · 2015: 97 · 2014: 74 · 2013: 66 · 2012: 15
- FWCI
- 40.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Christopher and Dana Reeve Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Myelin Repair Foundation
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM049831, R01 GM 49831)
- National Institute of Neurological Disorders and Stroke (R01NS059893)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- reactive astrogliosis, reactive astrocytes, astrocyte phenotype, ischemic stroke, neuroinflammation, lipopolysaccharide, gene expression profiling, neutrophil gelatinase-associated lipocalin, Serpina3n, astrocyte subtypes, central nervous system injury, transcriptome
- MeSH terms
- Animals, Astrocytes, Brain, Brain Injuries, Disease Models, Animal, Gliosis, Nerve Tissue Proteins, Genome, Proteome, Gene Expression Profiling, Mice
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