Inflammatory Mediators Alter the Astrocyte Transcriptome and Calcium Signaling Elicited by Multiple G-Protein-Coupled Receptors
Open accessAbstract
Inflammation features in CNS disorders such as stroke, trauma, neurodegeneration, infection, and autoimmunity in which astrocytes play critical roles. To elucidate how inflammatory mediators alter astrocyte functions, we examined effects of transforming growth factor-β1 (TGF-β1), lipopolysaccharide (LPS), and interferon-gamma (IFNγ), alone and in combination, on purified, mouse primary cortical astrocyte cultures. We used microarrays to conduct whole-genome expression profiling, and measured calcium signaling, which is implicated in mediating dynamic astrocyte functions. Combinatorial exposure to TGF-β1, LPS, and IFNγ significantly modulated astrocyte expression of >6800 gene probes, including >380 synergistic changes not predicted by summing individual treatment effects. Bioinformatic analyses revealed significantly and markedly upregulated molecular networks and pathways associated in particular with immune signaling and regulation of cell injury, death, growth, and proliferation. Highly regulated genes included chemokines, growth factors, enzymes, channels, transporters, and intercellular and intracellular signal transducers. Notably, numerous genes for G-protein-coupled receptors (GPCRs) and G-protein effectors involved in calcium signaling were significantly regulated, mostly down (for example,Cxcr4,Adra2a,Ednra,P2ry1,Gnao1,Gng7), but some up (for example,P2ry14,P2ry6,Ccrl2,Gnb4). We tested selected cases and found that changes in GPCR gene expression were accompanied by significant, parallel changes in astrocyte calcium signaling evoked by corresponding GPCR-specific ligands. These findings identify pronounced changes in the astrocyte transcriptome induced by TGF-β1, LPS, and IFNγ, and show that these inflammatory stimuli upregulate astrocyte molecular networks associated with immune- and injury-related functions and significantly alter astrocyte calcium signaling stimulated by multiple GPCRs.
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Previous research has shown that the transcriptomic profile of astrocytes varies in response to different insults, e.g. long-term activation.
“Previous research has shown that the transcriptomic profile of astrocytes varies in response to different”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Hamby et al., 2012
The Results section ('Treatment-dependent global changes in gene expression profiles'; page unavailable) reports different astrocyte gene-expression changes under different inflammatory treatments. The Methods section ('Cytokine and endotoxin exposure'; page unavailable) describes exposures lasting hours to about two days, not long-term activation, so that example is not supported. (LLM, conf=0.85)
Experimental — accuracy not yet measuredFunctional studies showed increased expression of several receptors in astrocytes surrounding Aβ sites in both AD mouse models and post-mortem human AD brains, likely affecting downstream signaling and synaptic function.
“These studies showed an increased expression of several receptors in astrocytes surrounding Aβ sites in both AD mouse models and post-mortem human AD brains, likely affecting the downstream signaling and its synaptic function 93 .”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [93]
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References 71 · Cited by 228
- Authors
- Hamby, M. E., Coppola, G., Ao, Y., Geschwind, D. H., Khakh, B. S., & Sofroniew, M. V.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-10-17
- Volume
- 32
- Issue
- 42
- Pages
- 14489-14510
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3518872
- OpenAlex
- W2077134054
- Cited by
- 228
- References
- 71
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 31 · 2023: 9 · 2022: 10 · 2021: 16 · 2020: 22 · 2019: 20 · 2018: 16 · 2017: 14 · 2016: 15 · 2015: 18 · 2014: 18 · 2013: 14 · 2012: 1
- FWCI
- 8.14
- 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)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health
- University of California, Los Angeles
- National Institute of Mental Health (T32MH019925)
- National Institute of Neurological Disorders and Stroke (NS071292, R21NS063186, NS057624, NS060677, R01NS060677, NS063186, R21NS071292, R01NS057624, P30NS062691)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- astrocytes, astrocyte transcriptome, calcium signaling, G protein-coupled receptors, TGF-β1, lipopolysaccharide, interferon-gamma, neuroinflammation, cortical astrocytes, gene expression profiling, chemokines, immune signaling, synergistic gene regulation
- MeSH terms
- Animals, Animals, Newborn, Astrocytes, Cells, Cultured, Female, Interferon-gamma, Lipopolysaccharides, Male, Mice, Inbred C57BL, Down-Regulation, Up-Regulation, Inflammation Mediators, Calcium Signaling, Receptors, G-Protein-Coupled, Mice, Transforming Growth Factor beta1, Transcriptome
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