Microglial identity and inflammatory responses are controlled by the combined effects of neurons and astrocytes
Open accessAbstract
Microglia, brain-resident macrophages, require instruction from the CNS microenvironment to maintain their identity and morphology and regulate inflammatory responses, although what mediates this is unclear. Here, we show that neurons and astrocytes cooperate to promote microglial ramification, induce expression of microglial signature genes ordinarily lost in vitro and in age and disease in vivo, and repress infection- and injury-associated gene sets. The influence of neurons and astrocytes separately on microglia is weak, indicative of synergies between these cell types, which exert their effects via a mechanism involving transforming growth factor β2 (TGF-β2) signaling. Neurons and astrocytes also combine to provide immunomodulatory cues, repressing primed microglial responses to weak inflammatory stimuli (without affecting maximal responses) and consequently limiting the feedback effects of inflammation on the neurons and astrocytes themselves. These findings explain why microglia isolated ex vivo undergo de-differentiation and inflammatory deregulation and point to how disease- and age-associated changes may be counteracted.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Baxter et al. recently demonstrated that co-culture with both neurons and astrocytes reduces microglial activation compared to monoculture, and co-culture with only neurons or only astrocytes.
“Baxter et al. [35] recently demonstrated that co-culture with both neurons and astrocytes reduces microglial activation compared to monoculture, and co-culture with only neurons or only astrocytes”
From Culture shock: microglial heterogeneity, activation, and disrupted single-cell microglial networks in vitro (2022) · cites this paper as [35]
The Results section, “Neurons and astrocytes regulate the microglial response to LPS” (page unavailable), reports that the combined co-culture suppressed microglial responses to low-dose LPS more strongly than monoculture or co-culture with either cell type alone. The claim omits that condition: the paper says combined co-culture did not reduce basal expression of LPS-response genes or their maximal LPS-induced levels. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe homeostatic phenotype is at least partly regulated by TGF-β2 signaling from astrocytes and neurons.
“A recent study [35] demonstrated that this homeostatic phenotype is at least partly regulated by TGF-β2 signaling from astrocytes and neurons”
From Culture shock: microglial heterogeneity, activation, and disrupted single-cell microglial networks in vitro (2022) · cites this paper as [35]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979 · see citing works
Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543 · see citing works
Hammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., Walker, A. J., Segel, M., Nemesh, J., Saunders, A., et al. (2018) · doi:10.1101/406140 · Cited by 2,225 · see citing works
How neuroinflammation contributes to neurodegeneration
Ransohoff, R. M. (2016) · Science · doi:10.1126/science.aag2590 · Cited by 1,967 · cited 2× · see citing works
“…of microglia function contributes to or drives the pathogenesis of certain neurodevelopmental and psychiatric diseases such as autism and schizophrenia, as well as neurodegenerative diseases, including Alzheimer’s disease (AD) (Perry and Holmes, 2014; Ransohoff, 2016; Salter and Stevens, 2017).”
BackgroundAn environment-dependent transcriptional network specifies human microglia identity
Gosselin, D., Skola, D., Coufal, N. G., Holtman, I. R., Schlachetzki, J. C. M., Sajti, E., Jaeger, B. N., O’Connor, C., Fitzpatrick, C., Pasillas, M. P., et al. (2017) · Science · doi:10.1126/science.aal3222 · Cited by 1,220 · cited 13× · see citing works
“…We investigated, using our mixed-species RNA-seq approach (Qiu et al., 2018), whether neurons and astrocytes can promote expression of mature microglial signature genes ordinarily lost when microglia are maintained in vitro (Bohlen et al., 2017; Gosselin et al., 2017; Stansley et al., 2012).”
BackgroundMethodInfluentialApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Initiative, A. D. N., Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., Tsai, R. M., Spina, S., Grinberg, L. T., et al. (2017) · Nature · doi:10.1038/nature24016 · Cited by 1,220 · see citing works
Microglia development follows a stepwise program to regulate brain homeostasis
Matcovitch-Natan, O., Winter, D. R., Giladi, A., Vargas Aguilar, S., Spinrad, A., Sarrazin, S., Ben-Yehuda, H., David, E., Zelada González, F., Perrin, P., et al. (2016) · Science · doi:10.1126/science.aad8670 · Cited by 1,180 · see citing works
Lin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.008 · Cited by 1,125 · see citing works
Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis
Zrzavy, T., Hametner, S., Wimmer, I., Butovsky, O., Weiner, H. L., & Lassmann, H. (2017) · Brain · doi:10.1093/brain/awx113 · Cited by 684 · see citing works
Bohlen, C. J., Bennett, F. C., Tucker, A. F., Collins, H. Y., Mulinyawe, S. B., & Barres, B. A. (2017) · Neuron · doi:10.1016/j.neuron.2017.04.043 · Cited by 676 · see citing works
Friedman, B. A., Srinivasan, K., Ayalon, G., Meilandt, W. J., Lin, H., Huntley, M. A., Cao, Y., Lee, S.-H., Haddick, P. C. G., Ngu, H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.066 · Cited by 662 · cited 4× · see citing works
“We took advantage of a meta-analysis that identified seven coregulated gene sets in isolatedmicroglia across a variety of neurodegenerative, inflammatory, neoplastic, and infectious disease models (Friedman et al., 2018).”
BackgroundInfluentialMicroglia: Dynamic Mediators of Synapse Development and Plasticity
Wu, Y., Dissing-Olesen, L., MacVicar, B. A., & Stevens, B. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.08.008 · Cited by 661 · see citing works
Stansley, B., Post, J., & Hensley, K. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-115 · Cited by 419 · see citing works
Schiweck, J., Eickholt, B. J., & Murk, K. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00261 · Cited by 223 · see citing works
Flagged first, then by citations
Research works printed but not linked: 37
- Basrai H.S. Christie K.J. Turbic A. Bye N. Turnley A.M. Suppressor of Cytokine Signaling-2 (SOCS2) Regulates the Microglial Response and Improves Functional Outcome after Traumatic Brain Injury in Mice PLoS ONE 11 2016 e0153418 27071013 PMC4829250
- Baxter P.S. Martel M.A. McMahon A. Kind P.C. Hardingham G.E. Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1 J. Neurochem. 118 2011 365 378 21623792 PMC3557719
- Bell K.F. Hardingham G.E. The influence of synaptic activity on neuronal health Curr. Opin. Neurobiol. 21 2011 299 305 21292474 PMC3160470
- Cox J. Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification Nat. Biotechnol. 26 2008 1367 1372 19029910
- Dobin A. Davis C.A. Schlesinger F. Drenkow J. Zaleski C. Jha S. Batut P. Chaisson M. Gingeras T.R. STAR: ultrafast universal RNA-seq aligner Bioinformatics 29 2013 15 21 23104886 PMC3530905
- Gordon S. Plüddemann A. Martinez Estrada F. Macrophage heterogeneity in tissues: phenotypic diversity and functions Immunol. Rev. 262 2014 36 55 25319326 PMC4231239
- Hasel P. Dando O. Jiwaji Z. Baxter P. Todd A.C. Heron S. Márkus N.M. McQueen J. Hampton D.W. Torvell M. Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism Nat. Commun. 8 2017 15132 28462931 PMC5418577
- Hirbec H. Marmai C. Duroux-Richard I. Roubert C. Esclangon A. Croze S. Lachuer J. Peyroutou R. Rassendren F. The microglial reaction signature revealed by RNAseq from individual mice Glia 66 2018 971 986 29399880
- Hoarau J.J. Krejbich-Trotot P. Jaffar-Bandjee M.C. Das T. Thon-Hon G.V. Kumar S. Neal J.W. Gasque P. Activation and control of CNS innate immune responses in health and diseases: a balancing act finely tuned by neuroimmune regulators (NIReg) CNS Neurol. Disord. Drug Targets 10 2011 25 43 21143144
- Kuleshov M.V. Jones M.R. Rouillard A.D. Fernandez N.F. Duan Q. Wang Z. Koplev S. Jenkins S.L. Jagodnik K.M. Lachmann A. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update Nucleic Acids Res. 44 W1 2016 W90 7 27141961 PMC4987924
- Lavin Y. Winter D. Blecher-Gonen R. David E. Keren-Shaul H. Merad M. Jung S. Amit I. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment Cell 159 2014 1312 1326 25480296 PMC4437213
- Liddelow S.A. Barres B.A. Reactive Astrocytes: Production, Function, and Therapeutic Potential Immunity 46 2017 957 967 28636962
- Lively S. Schlichter L.C. Microglia Responses to Pro-inflammatory Stimuli (LPS, IFNγ+TNFα) and Reprogramming by Resolving Cytokines (IL-4, IL-10) Front. Cell. Neurosci. 12 2018 215 30087595 PMC6066613
- Love M.I. Huber W. Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 15 2014 550 25516281 PMC4302049
- Martel M.A. Ryan T.J. Bell K.F. Fowler J.H. McMahon A. Al-Mubarak B. Komiyama N.H. Horsburgh K. Kind P.C. Grant S.G. The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults Neuron 74 2012 543 556 22578505 PMC3398391
- Michaud J.P. Hallé M. Lampron A. Thériault P. Préfontaine P. Filali M. Tribout-Jover P. Lanteigne A.M. Jodoin R. Cluff C. Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology Proc. Natl. Acad. Sci. USA 110 2013 1941 1946 23322736 PMC3562771
- Nimmerjahn A. Kirchhoff F. Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo Science 308 2005 1314 1318 15831717
- Okaty B.W. Sugino K. Nelson S.B. Cell type-specific transcriptomics in the brain J. Neurosci. 31 2011 6939 6943 21562254 PMC3142746
- Okaty B.W. Sugino K. Nelson S.B. A quantitative comparison of cell-type-specific microarray gene expression profiling methods in the mouse brain PLoS ONE 6 2011 e16493 21304595 PMC3029380
- Papadia S. Soriano F.X. Léveillé F. Martel M.A. Dakin K.A. Hansen H.H. Kaindl A. Sifringer M. Fowler J. Stefovska V. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses Nat. Neurosci. 11 2008 476 487 18344994 PMC2556874
- Perry V.H. Holmes C. Microglial priming in neurodegenerative disease Nat. Rev. Neurol. 10 2014 217 224 24638131
- Poltorak A. He X. Smirnova I. Liu M.Y. Van Huffel C. Du X. Birdwell D. Alejos E. Silva M. Galanos C. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene Science 282 1998 2085 2088 9851930
- Puddifoot C. Martel M.A. Soriano F.X. Camacho A. Vidal-Puig A. Wyllie D.J. Hardingham G.E. PGC-1α negatively regulates extrasynaptic NMDAR activity and excitotoxicity J. Neurosci. 32 2012 6995 7000 22593067 PMC3359835
- Pulido-Salgado M. Vidal-Taboada J.M. Barriga G.G. Solà C. Saura J. RNA-Seq transcriptomic profiling of primary murine microglia treated with LPS or LPS + IFNγ Sci. Rep. 8 2018 16096 30382133 PMC6208373
- Qiu J. Dando O. Baxter P.S. Hasel P. Heron S. Simpson T.I. Hardingham G.E. Mixed-species RNA-seq for elucidation of non-cell-autonomous control of gene transcription Nat. Protoc. 13 2018 2176 2199 30250293
- Rappsilber J. Ishihama Y. Mann M. Stop and go extraction tips for matrix-assisted laser desorption/ionization, nanoelectrospray, and LC/MS sample pretreatment in proteomics Anal. Chem. 75 2003 663 670 12585499
- Salter M.W. Stevens B. Microglia emerge as central players in brain disease Nat. Med. 23 2017 1018 1027 28886007
- Sievers J. Parwaresch R. Wottge H.U. Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: morphology Glia 12 1994 245 258 7890329
- Slaker M.L. Harkness J.H. Sorg B.A. A standardized and automated method of perineuronal net analysis using Wisteria floribunda agglutinin staining intensity IBRO Rep. 1 2016 54 60 28713865 PMC5507617
- Srinivasan K. Friedman B.A. Larson J.L. Lauffer B.E. Goldstein L.D. Appling L.L. Borneo J. Poon C. Ho T. Cai F. Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses Nat. Commun. 7 2016 11295 27097852 PMC4844685
- Stuart T. Butler A. Hoffman P. Hafemeister C. Papalexi E. Mauck W.M. 3rd Hao Y. Stoeckius M. Smibert P. Satija R. Comprehensive Integration of Single-Cell Data Cell 177 2019 1888 1902 e1821 31178118 PMC6687398
- Tanaka J. Maeda N. Microglial ramification requires nondiffusible factors derived from astrocytes Exp. Neurol. 137 1996 367 375 8635553
- Tzioras M. Davies C. Newman A. Jackson R. Spires-Jones T. Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer’s disease Neuropathol. Appl. Neurobiol. 45 2018 327 346 30394574 PMC6563457
- UniProt Consortium UniProt: a worldwide hub of protein knowledge Nucleic Acids Res. 47 D1 2019 D506 D515 30395287 PMC6323992
- van den Brink S.C. Sage F. Vértesy Á. Spanjaard B. Peterson-Maduro J. Baron C.S. Robin C. van Oudenaarden A. Single-cell sequencing reveals dissociation-induced gene expression in tissue subpopulations Nat. Methods 14 2017 935 936 28960196
- Wylot B. Konarzewska K. Bugajski L. Piwocka K. Zawadzka M. Isolation of vascular endothelial cells from intact and injured murine brain cortex-technical issues and pitfalls in FACS analysis of the nervous tissue Cytometry A 87 2015 908 920 25892199
- Zhang Y. Sloan S.A. Clarke L.E. Caneda C. Plaza C.A. Blumenthal P.D. Vogel H. Steinberg G.K. Edwards M.S. Li G. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse Neuron 89 2016 37 53 26687838 PMC4707064
Cited by
Sorted by citations
Mou, Y., Du, Y., Zhou, L., Yue, J., Hu, X., Liu, Y., Chen, S., Lin, X., Zhang, G., Xiao, H., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.796288 · Cited by 432 · see citing works
Assembloid models of cell-cell interaction to study tissue and disease biology
Onesto, M. M., Kim, J.-I., & Pasca, S. P. (2024) · Cell Stem Cell · doi:10.1016/j.stem.2024.09.017 · Cited by 107 · see citing works
Cadiz, M. P., Jensen, T. D., Sens, J. P., Zhu, K., Song, W.-M., Zhang, B., Ebbert, M., Chang, R., & Fryer, J. D. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00531-1 · Cited by 73 · see citing works
Yin, Y., Lv, G., Zhang, W., Yuan, J., Yang, Y., Wang, Y., Liu, S., Wang, S., Yan, B., Bo, H., et al. (2023) · Behavioural Brain Research · doi:10.1016/j.bbr.2023.114326 · Cited by 9 · see citing works
Deep Trans-Omic Network Fusion for Molecular Mechanism of Alzheimer’s Disease
Xie, L., Raj, Y., Varathan, P., He, B., Yu, M., Nho, K., Salama, P., Saykin, A. J., & Yan, J. (2024) · Journal of Alzheimer's Disease · doi:10.3233/jad-240098 · Cited by 2 · see citing works
- Authors
- Baxter, P. S., Dando, O., Emelianova, K., He, X., McKay, S., Hardingham, G. E., & Qiu, J.
- Affiliations
- UK Dementia Research Institute (GB)
- Corresponding author
- Hardingham, Giles E.
- Qiu, Jing
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 34
- Issue
- 12
- Pages
- 108882
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7994374
- OpenAlex
- W3136276111
- Cited by
- 122
- References
- 14
- Citations by year
- 2026: 18 · 2025: 16 · 2024: 23 · 2023: 21 · 2022: 32 · 2021: 12
- FWCI
- 8.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Simons Initiative for the Developing Brain
- Medical Research Council
- UK Dementia Research Institute
- Alzheimer's Society
- Wellcome Trust
- Alzheimer’s Research UK
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, microglia-neuron interaction, astrocyte-microglia interaction, microglial ramification, TGF-β2 signaling, neuroinflammation, immunomodulation, aging
- MeSH terms
- Animals, Astrocytes, Gene Expression Regulation, Multigene Family, Homeostasis, Humans, Inflammation, Interferons, Lipopolysaccharides, Neurons, Phagocytosis, Signal Transduction, Transforming Growth Factor beta, Microglia, Gene Expression Profiling, Mice, Rats, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
