Sofroniew, M. V. & Vinters, H. V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).
Burda, J. E. & Sofroniew, M. V. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81, 229–248 (2014).
Linnerbauer, M., Wheeler, M. A. & Quintana, F. J. Astrocyte crosstalk in CNS inflammation. Neuron 108, 608–622 (2020).
Escartin, C. et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24, 312–325 (2021).
Allen, N. J. & Eroglu, C. Cell biology of astrocyte-synapse interactions. Neuron 96, 697–708 (2017).
Haim, L. B. & Rowitch, D. H. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 18, 31–41 (2017).
Khakh, B. S. & Deneen, B. The emerging nature of astrocyte diversity. Annu. Rev. Neurosci. 42, 187–207 (2019).
Lu, T. Y. et al. Axon degeneration induces glial responses through Draper-TRAF4-JNK signalling. Nat. Commun. 8, 14355 (2017).
Sofroniew, M. V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263 (2015).
Khakh, B. S. & Sofroniew, M. V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942–952 (2015).
Yu, X. et al. Context-specific striatal astrocyte molecular responses are phenotypically exploitable. Neuron 108, 1146–1162 (2020).
Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016).
Schreiner, B. et al. Astrocyte depletion impairs redox homeostasis and triggers neuronal loss in the adult CNS. Cell Rep. 12, 1377–1384 (2015).
Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020).
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y. & Greenleaf, W. J. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013).
Wanner, I. B. et al. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J. Neurosci. 33, 12870–12886 (2013).
Diaz-Castro, B., Bernstein, A. M., Coppola, G., Sofroniew, M. V. & Khakh, B. S. Molecular and functional properties of cortical astrocytes during peripherally induced neuroinflammation. Cell Rep. 36, 109508 (2021).
Inoue, F., Kreimer, A., Ashuach, T., Ahituv, N. & Yosef, N. Identification and massively parallel characterization of regulatory elements driving neural induction. Cell Stem Cell 25, 713–727 (2019).
Lattke, M. et al. Extensive transcriptional and chromatin changes underlie astrocyte maturation in vivo and in culture. Nat. Commun. 12, 4335 (2021).
Granja, J. M. et al. ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis. Nat. Genet. 53, 403–411 (2021).
Schep, A. N., Wu, B., Buenrostro, J. D. & Greenleaf, W. J. chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nat. Methods 14, 975–978 (2017).
Wingelhofer, B. et al. Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer. Leukemia 32, 1713–1726 (2018).
Henry, C. J. et al. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J. Neuroinflamm. 5, 15 (2008).
Herrmann, J. E. et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J. Neurosci. 28, 7231–7243 (2008).
Wohlfahrt, T. et al. PU.1 controls fibroblast polarization and tissue fibrosis. Nature 566, 344–349 (2019).
Sofroniew, M. V. Astrocyte reactivity: subtypes, states, and functions in CNS innate immunity. Trends Immunol. 41, 758–770 (2020).
Diaz-Castro, B., Gangwani, M. R., Yu, X., Coppola, G. & Khakh, B. S. Astrocyte molecular signatures in Huntington’s disease. Sci. Transl. Med. 11, eaaw8546 (2019).
Sun, S. Y. et al. Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. Proc. Natl Acad. Sci. USA 112, E6993–E7002 (2015).
Sekar, S. et al. Alzheimer’s disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes. Neurobiol. Aging 36, 583–591 (2015).
Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020).
Kamphuis, W. et al. GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer’s disease. Glia 63, 1036–1056 (2015).
Boisvert, M. M., Erikson, G. A., Shokhirev, M. N. & Allen, N. J. The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep. 22, 269–285 (2018).
Rojo, A. I. et al. Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy. Redox Biol. 18, 173–180 (2018).
Oksanen, M. et al. NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human presenilin-1 mutated Alzheimer’s disease astrocytes. Glia 68, 589–599 (2020).
Laug, D. et al. Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury. J. Clin. Invest. 129, 4408–4418 (2019).
Venkatesh, I. et al. Co-occupancy identifies transcription factor co-operation for axon growth. Nat. Commun. 12, 2555 (2021).
Garcia, A. D. R., Doan, N. B., Imura, T., Bush, T. G. & Sofroniew, M. V. GFAP-expressing progenitors are the principle source of constitutive neurogenesis in adult mouse forebrain. Nat. Neurosci. 7, 1233–1241 (2004).
Sanz, E. et al. Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc. Natl Acad. Sci. USA 106, 13939–13944 (2009).
Sumi-Ichinose, C., Ichinose, H., Metzger, D. & Chambon, P. SNF2β-BRG1 is essential for the viability of F9 murine embryonal carcinoma cells. Mol. Cell. Biol. 17, 5976–5986 (1997).
Metz, G. A. & Whishaw, I. Q. The ladder rung walking task: a scoring system and its practical application. J. Vis. Exp. https://doi.org/10.3791/1204 (2009).
Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 (2008).
Sukoff Rizzo, S. J. et al. Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes. Transl. Psychiatry 2, e199 (2012).
Lachmann, A. et al. ChEA: transcription factor regulation inferred from integrating genome-wide ChIP-X experiments. Bioinformatics 26, 2438–2444 (2010).
Fornes, O. et al. JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 48, D87–D92 (2020).
Matys, V. et al. TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 31, 374–378 (2003).
Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90–W97 (2016).
Krishnaswami, S. R. et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat. Protoc. 11, 499–524 (2016).
Bhattacharyya, S., Sathe, A. A., Bhakta, M., Xing, C. & Munshi, N. V. PAN-INTACT enables direct isolation of lineage-specific nuclei from fibrous tissues. PLoS ONE 14, e0214677 (2019).
Batiuk, M. Y. et al. An immunoaffinity-based method for isolating ultrapure adult astrocytes based on ATP1B2 targeting by the ACSA-2 antibody. J. Biol. Chem. 292, 8874–8891 (2017).
Cusanovich, D. A. et al. Multiplex single cell profiling of chromatin accessibility by combinatorial cellular indexing. Science 348, 910–914 (2015).
Deschamps, S. et al. Chromatin loop anchors contain core structural components of the gene expression machinery in maize. BMC Genom. 22, 23 (2021).
Weirauch, M. T. et al. Determination and inference of eukaryotic transcription factor sequence specificity. Cell 158, 1431–1443 (2014).
Kheradpour, P. & Kellis, M. Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 42, 2976–2987 (2014).
Courtine, G. et al. Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nat. Neurosci. 12, 1333–1342 (2009).
Neve, L. D., Savage, A. A., Koke, J. R. & Garcia, D. M. Activating transcription factor 3 and reactive astrocytes following optic nerve injury in zebrafish. Comp. Biochem. Physiol. C 155, 213–218 (2012).
Kim, K. H., Jeong, J. Y., Surh, Y. J. & Kim, K. W. Expression of stress-response ATF3 is mediated by Nrf2 in astrocytes. Nucleic Acids Res. 38, 48–59 (2010).
Koyama, Y. et al. Endothelin-1 stimulates expression of cyclin D1 and S-phase kinase-associated protein 2 by activating the transcription factor STAT3 in cultured rat astrocytes. J. Biol. Chem. 294, 3920–3933 (2019).
Cardinaux, J. R., Allaman, I. & Magistretti, P. J. Pro-inflammatory cytokines induce the transcription factors C/EBPbeta and C/EBPdelta in astrocytes. Glia 29, 91–97 (2000).
Ko, C. Y. et al. Glycogen synthase kinase-3β-mediated CCAAT/enhancer-binding protein delta phosphorylation in astrocytes promotes migration and activation of microglia/macrophages. Neurobiol. Aging 35, 24–34 (2014).
Pardo, L. et al. Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury. Glia 64, 853–874 (2016).
Zou, F. et al. Different functions of HIPK2 and CtBP2 in traumatic brain injury. J. Mol. Neurosci. 49, 395–408 (2013).
Robinson, K. F., Narasipura, S. D., Wallace, J., Ritz, E. M. & Al-Harthi, L. Negative regulation of IL-8 in human astrocytes depends on beta-catenin while positive regulation is mediated by TCFs/LEF/ATF2 interaction. Cytokine 136, 155252 (2020).
Yang, C. et al. β-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas. Proc. Natl Acad. Sci. USA 109, 6963–6968 (2012).
Wu, J. F. et al. Ablation of the transcription factors E2F1-2 limits neuroinflammation and associated neurological deficits after contusive spinal cord injury. Cell Cycle 14, 3698–3712 (2015).
Beck, H., Semisch, M., Culmsee, C., Plesnila, N. & Hatzopoulos, A. K. Egr-1 regulates expression of the glial scar component phosphacan in astrocytes after experimental stroke. Am. J. Pathol. 173, 77–92 (2008).
Mayer, S. I., Rossler, O. G., Endo, T., Charnay, P. & Thiel, G. Epidermal-growth-factor-induced proliferation of astrocytes requires Egr transcription factors. J. Cell Sci. 122, 3340–3350 (2009).
Wang, H. H., Hsieh, H. L., Wu, C. Y. & Yang, C. M. Oxidized low-density lipoprotein-induced matrix metalloproteinase-9 expression via PKC-delta/p42/p44 MAPK/Elk-1 cascade in brain astrocytes. Neurotox. Res. 17, 50–65 (2010).
Gerhauser, I., Alldinger, S. & Baumgartner, W. Ets-1 represents a pivotal transcription factor for viral clearance, inflammation, and demyelination in a mouse model of multiple sclerosis. J. Neuroimmunol. 188, 86–94 (2007).
Hashimoto, K. et al. Long-term activation of c-Fos and c-Jun in optic nerve head astrocytes in experimental ocular hypertension in monkeys and after exposure to elevated pressure in vitro. Brain Res. 1054, 103–115 (2005).
Yang, C. C., Hsiao, L. D. & Yang, C. M. Galangin inhibits LPS-induced MMP-9 expression via suppressing protein kinase-dependent AP-1 and FoxO1 activation in rat brain astrocytes. J. Inflamm. Res. 13, 945–960 (2020).
Cui, M., Huang, Y., Tian, C., Zhao, Y. & Zheng, J. FOXO3a inhibits TNF-α- and IL-1β-induced astrocyte proliferation: implication for reactive astrogliosis. Glia 59, 641–654 (2011).
Kizil, C. et al. Regenerative neurogenesis from neural progenitor cells requires injury-induced expression of Gata3. Dev. Cell 23, 1230–1237 (2012).
Garcia, A. D., Petrova, R., Eng, L. & Joyner, A. L. Sonic hedgehog regulates discrete populations of astrocytes in the adult mouse forebrain. J. Neurosci. 30, 13597–13608 (2010).
Du, F. et al. Hyperthermic preconditioning protects astrocytes from ischemia/reperfusion injury by up-regulation of HIF-1 alpha expression and binding activity. Biochim. Biophys. Acta 1802, 1048–1053 (2010).
Choi, K., Ni, L. & Jonakait, G. M. Fas ligation and tumor necrosis factor alpha activation of murine astrocytes promote heat shock factor-1 activation and heat shock protein expression leading to chemokine induction and cell survival. J. Neurochem. 116, 438–448 (2011).
Tzeng, S. F., Kahn, M., Liva, S. & De Vellis, J. Tumor necrosis factor-α regulation of the Id gene family in astrocytes and microglia during CNS inflammatory injury. Glia 26, 139–152 (1999).
Aronica, E. et al. Expression of Id proteins increases in astrocytes in the hippocampus of epileptic rats. Neuroreport 12, 2461–2465 (2001).
Jarosinski, K. W. & Massa, P. T. Interferon regulatory factor-1 is required for interferon-γ-induced MHC class I genes in astrocytes. J. Neuroimmunol. 122, 74–84 (2002).
Tarassishin, L. et al. Interferon regulatory factor 3 inhibits astrocyte inflammatory gene expression through suppression of the proinflammatory miR-155 and miR-155*. Glia 59, 1911–1922 (2011).
Gadea, A., Schinelli, S. & Gallo, V. Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. J. Neurosci. 28, 2394–2408 (2008).
Park, J. H. et al. Induction of Kruppel-like factor 4 expression in reactive astrocytes following ischemic injury in vitro and in vivo. Histochem. Cell Biol. 141, 33–42 (2014).
Jeong, K. H., Lee, K. E., Kim, S. Y. & Cho, K. O. Upregulation of Kruppel-like factor 6 in the mouse hippocampus after pilocarpine-induced status epilepticus. Neuroscience 186, 170–178 (2011).
Liu, F., Ni, J. J., Huang, J. J., Kou, Z. W. & Sun, F. Y. VEGF overexpression enhances the accumulation of phospho-S292 MeCP2 in reactive astrocytes in the adult rat striatum following cerebral ischemia. Brain Res. 1599, 32–43 (2015).
Wang, F. et al. 2-Arachidonylglycerol protects primary astrocytes exposed to oxygen-glucose deprivation through a blockade of NDRG2 signaling and STAT3 phosphorylation. Rejuv. Res. 19, 215–222 (2016).
Perez-Ortiz, J. M. et al. Mechanical lesion activates newly identified NFATc1 in primary astrocytes: implication of ATP and purinergic receptors. Eur. J. Neurosci. 27, 2453–2465 (2008).
Yang, Y. et al. Hemoglobin pretreatment endows rat cortical astrocytes resistance to hemin-induced toxicity via Nrf2/HO-1 pathway. Exp. Cell. Res. 361, 217–224 (2017).
Brambilla, R. et al. Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury. J. Exp. Med. 202, 145–156 (2005).
LeComte, M. D., Shimada, I. S., Sherwin, C. & Spees, J. L. Notch1-STAT3-ETBR signaling axis controls reactive astrocyte proliferation after brain injury. Proc. Natl Acad. Sci. USA 112, 8726–8731 (2015).
Chen, X. L. et al. Effects of interleukin-6 and IL-6/AMPK signaling pathway on mitochondrial biogenesis and astrocytes viability under experimental septic condition. Int. Immunopharmacol. 59, 287–294 (2018).
Gutbier, S. et al. Prevention of neuronal apoptosis by astrocytes through thiol-mediated stress response modulation and accelerated recovery from proteotoxic stress. Cell Death Differ. 25, 2101–2117 (2018).
Chen, Y. et al. The basic helix-loop-helix transcription factor olig2 is critical for reactive astrocyte proliferation after cortical injury. J. Neurosci. 28, 10983–10989 (2008).
Koyama, Y. Signaling molecules regulating phenotypic conversions of astrocytes and glial scar formation in damaged nerve tissues. Neurochem. Int. 78, 35–42 (2014).
Steliga, A. et al. Transcription factor Pax6 is expressed by astroglia after transient brain ischemia in the rat model. Folia Neuropathol. 51, 203–213 (2013).
Guo, X. et al. The AMPK-PGC-1α signaling axis regulates the astrocyte glutathione system to protect against oxidative and metabolic injury. Neurobiol. Dis. 113, 59–69 (2018).
Diehl, J. A., Tong, W., Sun, G. & Hannink, M. Tumor necrosis factor-alpha-dependent activation of a RelA homodimer in astrocytes. Increased phosphorylation of RelA and MAD-3 precede activation of RelA. J. Biol. Chem. 270, 2703–2707 (1995).
Yoo, K. Y. et al. Time-course alterations of Toll-like receptor 4 and NF-κB p65, and their co-expression in the gerbil hippocampal CA1 region after transient cerebral ischemia. Neurochem. Res. 36, 2417–2426 (2011).
Gupta, A. S. et al. RelB controls adaptive responses of astrocytes during sterile inflammation. Glia 67, 1449–1461 (2019).
Li, H. et al. The deficiency of NRSF/REST enhances the pro-inflammatory function of astrocytes in a model of Parkinson’s disease. Biochim. Biophys. Acta 1866, 165590 (2020).
Marumo, T. et al. Notch signaling regulates nucleocytoplasmic Olig2 translocation in reactive astrocytes differentiation after ischemic stroke. Neurosci. Res. 75, 204–209 (2013).
Tanigaki, K. & Honjo, T. Two opposing roles of RBP-J in Notch signaling. Curr. Top. Dev. Biol. 92, 231–252 (2010).
Wong, J. K. et al. Attenuation of cerebral ischemic injury in Smad1 deficient mice. PLoS ONE 10, e0136967 (2015).
Law, A. K. T. et al. TGF-β1 induction of the adenine nucleotide translocator 1 in astrocytes occurs through Smads and Sp1 transcription factors. BMC Neurosci. 5, 1 (2004).
Chen, C. et al. Astrocyte-specific deletion of Sox2 promotes functional recovery after traumatic brain injury. Cereb. Cortex 29, 54–69 (2019).
Song, W. et al. Immunohistochemical staining of ERG and SOX9 as potential biomarkers of docetaxel response in patients with metastatic castration-resistant prostate cancer. Oncotarget 7, 83735–83743 (2016).
Mao, X., Moerman-Herzog, A. M., Wang, W. & Barger, S. W. Differential transcriptional control of the superoxide dismutase-2 κB element in neurons and astrocytes. J. Biol. Chem. 281, 35863–35872 (2006).
Haroon, F. et al. Gp130-dependent astrocytic survival is critical for the control of autoimmune central nervous system inflammation. J. Immunol. 186, 6521–6531 (2011).
Khorooshi, R., Babcock, A. A. & Owens, T. NF-κB-driven STAT2 and CCL2 expression in astrocytes in response to brain injury. J. Immunol. 181, 7284–7291 (2008).
Doherty, J. et al. PI3K signaling and Stat92E converge to modulate glial responsiveness to axonal injury. PLoS Biol. 12, e1001985 (2014).
Park, S. J. et al. Astrocytes, but not microglia, rapidly sense H2O2 via STAT6 phosphorylation, resulting in cyclooxygenase-2 expression and prostaglandin release. J. Immunol. 188, 5132–5141 (2012).
Lurbke, A. et al. Limited TCF7L2 expression in MS lesions. PLoS ONE 8, e72822 (2013).
Chung, Y. H. et al. Enhanced expression of p53 in reactive astrocytes following transient focal ischemia. Neurol. Res. 24, 324–328 (2002).
Huang, Z. H. et al. YAP is a critical inducer of SOCS3, preventing reactive astrogliosis. Cereb. Cortex 26, 2299–2310 (2016).
Vivinetto, A. L. et al. Zeb2 is a regulator of astrogliosis and functional recovery after CNS injury. Cell Rep. 31, 107834 (2020).
Itoh, N. et al. Cell-specific and region-specific transcriptomics in the multiple sclerosis model: focus on astrocytes. Proc. Natl Acad. Sci. USA 115, E302–E309 (2018).
Zamanian, J. L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012).
Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).