Barcoded viral tracing of single-cell interactions in central nervous system inflammation
Open accessAbstract
Single-cell analysis of CNS interactions: Despite their importance in the physiology and pathology of the central nervous system (CNS), few methods are available for the unbiased, systematic investigation of cell-to-cell interactions at single-cell resolution. Clark et al. developed RABID-seq, a method that combines barcoded viral tracing with single-cell RNA sequencing (see the Perspective by Silvin and Ginhoux). RABID-seq identified the axon guidance molecules Sema4D-PlexinB2 and EphrinB3-EphB3 as mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis and, potentially, multiple sclerosis. These studies also identified candidate therapeutic molecules for the modulation of microglia-astrocyte interactions in multiple sclerosis. Science , this issue p. eabf1230 ; see also p. 342
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?
A recent study in a mouse model of multiple sclerosis showed that Sema4D expressed by microglia can activate Plexin-B1 and -B2 expressed in astrocytes.
“A recent study in a mouse model of multiple sclerosis (MS) showed that Sema4D expressed by microglia can activate Plexin-B1 and -B2 expressed in astrocytes61.”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [61]
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
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria
Polman, C. H., Reingold, S. C., Banwell, B., Clanet, M., Cohen, J. A., Filippi, M., Fujihara, K., Havrdova, E., Hutchinson, M., Kappos, L., et al. (2011) · Annals of Neurology · doi:10.1002/ana.22366 · Cited by 9,802 · see citing works
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · see citing works
Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool
Chen, E. Y., Tan, C. M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G. V., Clark, N. R., & Ma’ayan, A. (2013) · BMC Bioinformatics · doi:10.1186/1471-2105-14-128 · Cited by 7,814 · see citing works
Aran, D., Looney, A. P., Liu, L., Wu, E., Fong, V., Hsu, A., Chak, S., Naikawadi, R. P., Wolters, P. J., Abate, A. R., et al. (2019) · Nature Immunology · doi:10.1038/s41590-018-0276-y · Cited by 4,984 · see citing works
Self-citationOptimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9
Doench, J. G., Fusi, N., Sullender, M., Hegde, M., Vaimberg, E. W., Donovan, K. F., Smith, I., Tothova, Z., Wilen, C., Orchard, R., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3437 · Cited by 4,637 · see citing works
Visualization and analysis of gene expression in tissue sections by spatial transcriptomics
Ståhl, P. L., Salmén, F., Vickovic, S., Lundmark, A., Navarro, J. F., Magnusson, J., Giacomello, S., Asp, M., Westholm, J. O., Huss, M., et al. (2016) · Science · doi:10.1126/science.aaf2403 · Cited by 3,834 · see citing works
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · see citing works
Molecular Architecture of the Mouse Nervous System
Zeisel, A., Hochgerner, H., Lönnerberg, P., Johnsson, A., Memic, F., van der Zwan, J., Häring, M., Braun, E., Borm, L. E., La Manno, G., et al. (2018) · Cell · doi:10.1016/j.cell.2018.06.021 · Cited by 2,995 · see citing works
Astrocyte scar formation aids central nervous system axon regeneration
Anderson, M. A., Burda, J. E., Ren, Y., Ao, Y., O’Shea, T. M., Kawaguchi, R., Coppola, G., Khakh, B. S., Deming, T. J., & Sofroniew, M. V. (2016) · Nature · doi:10.1038/nature17623 · Cited by 1,851 · see citing works
Molecular diversity and specializations among the cells of the adult mouse brain
Saunders, A., Macosko, E. Z., Wysoker, A., Goldman, M., Krienen, F. M., de Rivera, H., Bien, E., Baum, M., Bortolin, L., Wang, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.028 · Cited by 1,847 · see citing works
Three-dimensional intact-tissue sequencing of single-cell transcriptional states
Wang, X., Allen, W. E., Wright, M. A., Sylwestrak, E. L., Samusik, N., Vesuna, S., Evans, K., Liu, C., Ramakrishnan, C., Liu, J., et al. (2018) · Science · doi:10.1126/science.aat5691 · Cited by 1,620 · see citing works
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
Ulland, T. K., Song, W. M., Huang, S. C.-C., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y., Cairns, N. J., Kambal, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.023 · Cited by 1,263 · cited 1× · see citing works
“mTOR controls mitochondrial function (63), which has been linked to pathogenic activities of astrocytes and microglia in neurologic disorders (9, 64).”
BackgroundAstrocyte barriers to neurotoxic inflammation
Sofroniew, M. V. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3898 · Cited by 1,202 · see citing works
An updated histological classification system for multiple sclerosis lesions
Kuhlmann, T., Ludwin, S., Prat, A., Antel, J., Brück, W., & Lassmann, H. (2017) · Acta Neuropathologica · doi:10.1007/s00401-016-1653-y · Cited by 692 · see citing works
Self-citationNeuronal vulnerability and multilineage diversity in multiple sclerosis
Schirmer, L., Velmeshev, D., Holmqvist, S., Kaufmann, M., Werneburg, S., Jung, D., Vistnes, S., Stockley, J. H., Young, A., Steindel, M., et al. (2019) · Nature · doi:10.1038/s41586-019-1404-z · Cited by 638 · see citing works
Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling
Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y., & Pasquale, E. B. (2003) · Nature Neuroscience · doi:10.1038/nn994 · Cited by 516 · see citing works
Mildner, A., Mack, M., Schmidt, H., Brück, W., Djukic, M., Zabel, M. D., Hille, A., Priller, J., & Prinz, M. (2009) · Brain · doi:10.1093/brain/awp144 · Cited by 445 · see citing works
Self-citationMarsh, S. E., Walker, A. J., Kamath, T., Dissing-Olesen, L., Hammond, T. R., de Soysa, T. Y., Young, A. M. H., Murphy, S., Abdulraouf, A., Nadaf, N., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01022-8 · Cited by 432 · see citing works
Gadani, S. P., Walsh, J. T., Smirnov, I., Zheng, J., & Kipnis, J. (2015) · Neuron · doi:10.1016/j.neuron.2015.01.013 · Cited by 359 · cited 2× · see citing works
“S. P. Gadani, J. T. Walsh, I. Smirnov, J. Zheng, J. Kipnis, The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury.”
BackgroundKang, Z., Altuntas, C. Z., Gulen, M. F., Liu, C., Giltiay, N., Qin, H., Liu, L., Qian, W., Ransohoff, R. M., Bergmann, C., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.03.004 · Cited by 297 · see citing works
Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation
Kueh, H. Y., Champhekar, A., Nutt, S. L., Elowitz, M. B., & Rothenberg, E. V. (2013) · Science · doi:10.1126/science.1240831 · Cited by 273 · see citing works
Continuous and Discrete Neuron Types of the Adult Murine Striatum
Stanley, G., Gokce, O., Malenka, R. C., Südhof, T. C., & Quake, S. R. (2020) · Neuron · doi:10.1016/j.neuron.2019.11.004 · Cited by 158 · see citing works
Flagged first, then by citations
Research works printed but not linked: 106
- [3]Wheeler MA MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593– 599 (2020). doi: 10.1038/s41586-020-1999-0 32051591 PMC8049843 · DOI · Paper page
- [4]Greenhalgh AD, David S, Bennett FC, Immune cell regulation of glia during CNS injury and disease. Nat. Rev. Neurosci 21, 139– 152 (2020). doi: 10.1038/s41583-020-0263-9 32042145 · DOI
- [5]Mayo L. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat. Med 20, 1147– 1156 (2014). doi: 10.1038/nm.3681 25216636 PMC4255949 · DOI
- [6]Rothhammer V. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med 22, 586– 597 (2016). doi: 10.1038/nm.4106 27158906 PMC4899206 · DOI · Paper page
- [8]Wheeler MA, Quintana FJ, Regulation of Astrocyte Functions in Multiple Sclerosis. Cold Spring Harb. Perspect. Med 9, a029009 (2019). doi: 10.1101/cshperspect.a029009 29358321 PMC6314073 · DOI
- [9]Chao CC Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS. Cell 179, 1483– 1498.e22 (2019). doi: 10.1016/j.cell.2019.11.016 31813625 PMC6936326 · DOI
- [10]Sanmarco LM Gut-licensed IFNα+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes. Nature 590, 473– 479 (2021). doi: 10.1038/s41586-020-03116-4 33408417 PMC8039910 · DOI · Paper page
- [11]Vainchtein ID Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 359, 1269– 1273 (2018). doi: 10.1126/science.aal3589 29420261 PMC6070131 · DOI · Paper page
- [12]Rothhammer V. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724– 728 (2018). doi: 10.1038/s41586-018-0119-x 29769726 PMC6422159 · DOI · Paper page
- [13]Wheeler MA Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation. Cell 176, 581– 596.e18 (2019). doi: 10.1016/j.cell.2018.12.012 30661753 PMC6440749 · DOI
- [14]Fontana A, Fierz W, Wekerle H, Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature 307, 273– 276 (1984). doi: 10.1038/307273a0 6198590 · DOI
- [15]Sun D, Wekerle H, Ia-restricted encephalitogenic T lymphocytes mediating EAE lyse autoantigen-presenting astrocytes. Nature 320, 70– 72 (1986). doi: 10.1038/320070a0 2419764 · DOI
- [16]Locatelli G. Mononuclear phagocytes locally specify and adapt their phenotype in a multiple sclerosis model. Nat. Neurosci 21, 1196– 1208 (2018). doi: 10.1038/s41593-018-0212-3 30127427 · DOI · Paper page
- [17]Giladi A. Dissecting cellular crosstalk by sequencing physically interacting cells. Nat. Biotechnol 38, 629– 637 (2020). doi: 10.1038/s41587-020-0442-2 32152598 · DOI
- [18]Pasqual G. Monitoring T cell-dendritic cell interactions in vivo by intercellular enzymatic labelling. Nature 553, 496– 500 (2018). doi: 10.1038/nature25442 29342141 PMC5853129 · DOI
- [19]Turczyk BM Spatial Sequencing: A Perspective. J. Biomol. Tech 31, 44– 46 (2020). 32382252 PMC7192195
- [20]Stoeckius M. Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865– 868 (2017). doi: 10.1038/nmeth.4380 28759029 PMC5669064 · DOI · Paper page
- [21]Hagendorf N, Conzelmann KK, Pseudotyping of G-Gene-Deficient Rabies Virus. Cold Spring Harb. Protoc 2015, prot089417 (2015). doi: 10.1101/pdb.prot089417 26631128 · DOI
- [22]Mount CW, Yalçin B, Cunliffe-Koehler K, Sundaresh S, Monje M, Monosynaptic tracing maps brain-wide afferent oligodendrocyte precursor cell connectivity. eLife 8, e49291 (2019). doi: 10.7554/eLife.49291 31625910 PMC6800000 · DOI
- [23]Motori E Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell Metab. 18, 844– 859 (2013). doi: 10.1016/j.cmet.2013.11.005 24315370 · DOI · Paper page
- [24]Card JP, Pseudorabies virus infection of the rat central nervous system: Ultrastructural characterization of viral replication, transport, and pathogenesis. J. Neurosci 13, 2515– 2539 (1993). doi: 10.1523/JNEUROSCI.13-06-02515.1993 8388923 PMC6576492 · DOI
- [25]Wickersham IR Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 53, 639– 647 (2007). doi: 10.1016/j.neuron.2007.01.033 17329205 PMC2629495 · DOI
- [26]Wall NR, Wickersham IR, Cetin A, De La Parra M, Callaway EM, Monosynaptic circuit tracing in vivo through Cre-dependent targeting and complementation of modified rabies virus. Proc. Natl. Acad. Sci. U.S.A 107, 21848– 21853 (2010). doi: 10.1073/pnas.1011756107 21115815 PMC3003023 · DOI
- [27]Garcia AD, Doan NB, Imura T, Bush TG, Sofroniew MV, GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat. Neurosci 7, 1233– 1241 (2004). doi: 10.1038/nn1340 15494728 · DOI
- [28]Callaway EM, Luo L, Monosynaptic Circuit Tracing with Glycoprotein-Deleted Rabies Viruses. J. Neurosci 35, 8979– 8985 (2015). doi: 10.1523/JNEUROSCI.0409-15.2015 26085623 PMC4469731 · DOI
- [29]Reardon TR Rabies Virus CVS-N2c(ΔG) Strain Enhances Retrograde Synaptic Transfer and NeuronalViability. Neuron 89, 711– 724 (2016). doi: 10.1016/j.neuron.2016.01.004 26804990 PMC4760870 · DOI
- [31]Xie L, Choudhury GR, Winters A, Yang SH, Jin K, Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur. J. Immunol 45, 180– 191 (2015). doi: 10.1002/eji.201444823 25329858 PMC4293323 · DOI · Paper page
- [32]Mayo L. IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. Brain 139, 1939– 1957 (2016). doi: 10.1093/brain/aww113 27246324 PMC4939696 · DOI
- [33]Ito M. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 565, 246– 250 (2019). doi: 10.1038/s41586-018-0824-5 30602786 · DOI · Paper page
- [34]Vento-Tormo R. Single-cell reconstruction of the early maternal-fetal interface in humans. Nature 563, 347– 353 (2018). doi: 10.1038/s41586-018-0698-6 30429548 PMC7612850 · DOI · Paper page
- [35]Huang KW, Sabatini BL, Single-Cell Analysis of Neuroinflammatory Responses Following Intracranial Injection of G-Deleted Rabies Viruses. Front. Cell. Neurosci 14, 65 (2020). doi: 10.3389/fncel.2020.00065 32265666 PMC7098990 · DOI
- [36]Kumanogoh A, Kikutani H., Immunological functions of the neuropilins and plexins as receptors for semaphorins. Nat. Rev. Immunol 13, 802– 814 (2013). doi: 10.1038/nri3545 24319778 · DOI
- [37]Tamagnone L. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99, 71– 80 (1999). doi: 10.1016/S0092-8674(00)80063-X 10520995 · DOI
- [38]Elhabazi A, Delaire S, Bensussan A, Boumsell L, Bismuth G., Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis. J. Immunol 166, 4341– 4347 (2001). doi: 10.4049/jimmunol.166.7.4341 11254687 · DOI
- [39]Janssen BJC, Structural basis of semaphorin-plexin signalling. Nature 467, 1118– 1122 (2010). doi: 10.1038/nature09468 20877282 PMC3587840 · DOI
- [40]Zhu L., Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc. Natl. Acad. Sci. U.S.A 104, 1621– 1626 (2007). doi: 10.1073/pnas.0606344104 17244710 PMC1785259 · DOI
- [41]Fazzari P. Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis. BMC Dev. Biol 7, 55 (2007). doi: 10.1186/1471-213X-7-55 17519029 PMC1890291 · DOI · Paper page
- [42]Paldy E. Semaphorin 4C Plexin-B2 signaling in peripheral sensory neurons is pronociceptive in a model of inflammatory pain. Nat. Commun 8, 176 (2017). doi: 10.1038/s41467-017-00341-w 28765520 PMC5539317 · DOI
- [43]Kania A, Klein R, Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nat. Rev. Mol. Cell Biol 17, 240– 256 (2016). doi: 10.1038/nrm.2015.16 26790531 · DOI
- [44]Imondi R, Wideman C, Kaprielian Z, Complementary expression of transmembrane ephrins and their receptors in the mouse spinal cord: A possible role in constraining the orientation of longitudinally projecting axons. Development 127, 1397– 1410 (2000). 10704386
- [46]Brückner K, Pasquale EB, Klein R, Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 275, 1640– 1643 (1997). doi: 10.1126/science.275.5306.16407 9054357 · DOI
- [47]Cowan CA, Henkemeyer M, The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 413, 174– 179 (2001). doi: 10.1038/35093123 11557983 · DOI
- [48]Henkemeyer M. Nuk controls pathfinding of commissural axons in the mammalian central nervoussystem. Cell 86, 35– 46 (1996). doi: 10.1016/S0092-8674(00)80075-6 8689685 · DOI
- [49]Holland SJ Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 383, 722– 725 (1996). doi: 10.1038/383722a0 8878483 · DOI
- [50]Klein R, Bidirectional modulation of synaptic functions by Eph/ephrin signaling. Nat. Neurosci 12, 15– 20 (2009). doi: 10.1038/nn.2231 19029886 · DOI
- [51]Qiao L. Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett 19, 6122– 6126 (2009). doi: 10.1016/j.bmcl.2009.09.010 19783434 PMC2785710 · DOI
- [52]Kung A. Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3. J. Am. Chem. Soc 138, 10554– 10560 (2016). doi: 10.1021/jacs.6b05483 27478969 PMC7476666 · DOI
- [53]Lock C. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med 8, 500– 508 (2002). doi: 10.1038/nm0502-500 11984595 · DOI
- [54]Ye L. IL-1β and TNF-α induce neurotoxicity through glutamate production: A potential role for neuronal glutaminase. J. Neurochem 125, 897– 908 (2013). doi: 10.1111/jnc.12263 23578284 PMC3747774 · DOI
- [55]Hewett SJ, Csernansky CA, Choi DW, Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS. Neuron 13, 487– 494 (1994). doi: 10.1016/0896-6273(94)90362-X 7520256 · DOI
- [56]Weiss JM, Berman JW, Astrocyte expression of monocyte chemoattractant protein-1 is differentially regulated by transforming growth factor beta. J. Neuroimmunol 91, 190– 197 (1998). doi: 10.1016/S0165-5728(98)00183-0 9846835 · DOI
- [57]Alvarez JI, The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727– 1731 (2011). doi: 10.1126/science.1206936 22144466 · DOI · Paper page
- [58]Rothhammer V. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc. Natl. Acad. Sci. U.S.A 114, 2012– 2017 (2017). doi: 10.1073/pnas.1615413114 28167760 PMC5338419 · DOI
- [59]Simmons SB, Pierson ER, Lee SY, Goverman JM, Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol. 34, 410– 422 (2013). doi: 10.1016/j.it.2013.04.006 23707039 PMC3752929 · DOI
- [60]Fruman DA The PI3K Pathway in Human Disease. Cell 170, 605– 635 (2017). doi: 10.1016/j.cell.2017.07.029 28802037 PMC5726441 · DOI · Paper page
- [61]Inoki K, Li Y, Zhu T, Wu J, Guan KL, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol 4, 648– 657 (2002). doi: 10.1038/ncb839 12172553 · DOI · Paper page
- [62]Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH, RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35– 43 (1994). doi: 10.1016/0092-8674(94)90570-3 7518356 · DOI · Paper page
- [63]Cunningham JT mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450, 736– 740 (2007). doi: 10.1038/nature06322 18046414 · DOI · Paper page
- [65]Bulua AC Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J. Exp. Med 208, 519– 533 (2011). doi: 10.1084/jem.20102049 21282379 PMC3058571 · DOI · Paper page
- [66]Ip WKE, Hoshi N, Shouval DS, Snap per S, Medzhitov R, Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513– 519 (2017). doi: 10.1126/science.aal3535 28473584 PMC6260791 · DOI
- [67]Mendiola AS Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation. Nat. Immunol 21, 513– 524 (2020). doi: 10.1038/s41590-020-0654-0 32284594 PMC7523413 · DOI · Paper page
- [68]Li N. Mitochon drial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J. Biol. Chem 278, 8516– 8525 (2003). doi: 10.1074/jbc.M210432200 12496265 · DOI
- [69]Sarafian TA Disruption of astrocyte STAT3 signaling decreases mitochondrial function and increases oxidative stress in vitro. PLOS ONE 5, e9532 (2010). doi: 10.1371/journal.pone.0009532 20224768 PMC2835741 · DOI
- [70]Wang L. Mitochondrial Respiratory Chain Inhibitors Involved in ROS Production Induced by Acute High Concentrations of Iodide and the Effects of SOD as a Protective Factor. Oxid. Med. Cell. Longev 2015, 217670 (2015). doi: 10.1155/2015/217670 26294939 PMC4532905 · DOI
- [72]Moffitt JR Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science 362, eaau5324 (2018). doi: 10.1126/science.aau5324 30385464 PMC6482113 · DOI · Paper page
- [73]Lee JH Fluorescent in situ sequencing (FISSEQ) of RNA for gene expression profiling in intact cells and tissues. Nat. Protoc 10, 442– 458 (2015). doi: 10.1038/nprot.2014.191 25675209 PMC4327781 · DOI · Paper page
- [74]Rodriques SG Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution. Science 363, 1463– 1467 (2019). doi: 10.1126/science.aaw1219 30923225 PMC6927209 · DOI · Paper page
- [76]Chen KH, Boettiger AN, Moffitt JR, Wang S, Zhuang X, RNA imaging. Spatially resolved, highly multiplexed RNA profiling in single cells. Science 348, aaa6090 (2015). doi: 10.1126/science.aaa6090 25858977 PMC4662681 · DOI · Paper page
- [77]Lee JH Highly multiplexed subcellular RNA sequencing in situ. Science 343, 1360– 1363 (2014). doi: 10.1126/science.1250212 24578530 PMC4140943 · DOI · Paper page
- [78]Zador AM Sequencing the connectome. PLOS Biol. 10, e1001411 (2012). doi: 10.1371/journal.pbio.1001411 23109909 PMC3479097 · DOI
- [79]Vainchtein ID, Molofsky AV, Astrocytes and Microglia: In Sickness and in Health. Trends Neurosci. 43, 144– 154 (2020). doi: 10.1016/j.tins.2020.01.003 32044129 PMC7472912 · DOI · Paper page
- [80]Nishide M, Kumanogoh A, The role of semaphorins in immune responses and autoimmune rheumatic diseases. Nat. Rev. Rheumatol 14, 19– 31 (2018). doi: 10.1038/nrrheum.2017.201 29213125 · DOI
- [81]Neufeld G, Kessler O, The semaphorins: Versatile regulators of tumour progression and tumour angiogenesis. Nat. Rev. Cancer 8, 632– 645 (2008). doi: 10.1038/nrc2404 18580951 · DOI
- [82]Tran TS, Kolodkin AL, Bharadwaj R, Semaphorin regulation of cellular morphology. Annu. Rev. Cell Dev. Biol 23, 263– 292 (2007). doi: 10.1146/annurev.cellbio.22.010605.093554 17539753 · DOI · Paper page
- [83]Pasterkamp RJ, Getting neural circuits into shape with semaphorins. Nat. Rev. Neurosci 13, 605– 618 (2012). doi: 10.1038/nrn3302 22895477 · DOI
- [84]Kumanogoh A. Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. J. Immunol 169, 1175– 1181 (2002). doi: 10.4049/jimmunol.169.3.1175 12133937 · DOI
- [85]Okuno T. Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. J. Immunol 184, 1499– 1506 (2010). doi: 10.4049/jimmunol.0903302 20038643 · DOI · Paper page
- [86]Worzfeld T, Offermanns S, Semaphorins and plexins as therapeutic targets. Nat. Rev. Drug Discov 13, 603– 621 (2014). doi: 10.1038/nrd4337 25082288 · DOI
- [87]Linnerbauer M, Wheeler MA, Quintana FJ, Astrocyte Crosstalk in CNS Inflammation. Neuron 108, 608– 622 (2020). doi: 10.1016/j.neuron.2020.08.012 32898475 PMC7704785 · DOI · Paper page
- [88]Lu P, Shih C, Qi H, Ephrin B1-mediated repulsion and signaling control germinal center T cell territoriality and function. Science 356, eaai9264 (2017). doi: 10.1126/science.aai9264 28408722 · DOI
- [89]Batlle E. EphB receptor activity suppresses colorectal cancer progression. Nature 435, 1126– 1130 (2005). doi: 10.1038/nature03626 15973414 · DOI
- [90]Contractor A. Trans-synaptic Eph receptor-ephrin signaling in hippocampal mossy fiber LTP. Science 296, 1864– 1869 (2002). doi: 10.1126/science.1069081 12052960 · DOI
- [91]Lim BK, Matsuda N, Poo MM, Ephrin-B reverse signaling promotes structural and functional synaptic maturation in vivo. Nat. Neurosci 11, 160– 169 (2008). doi: 10.1038/nn2033 18193042 · DOI
- [92]McClelland AC, Sheffler-Collins SI, Kayser MS, Dalva MB, Ephrin-B1 and ephrin-B2 mediate EphB-dependent presynaptic development via syntenin-1. Proc. Natl. Acad. Sci. U.S.A 106, 20487– 20492 (2009). doi: 10.1073/pnas.0811862106 19915143 PMC2787153 · DOI
- [93]Carmona MA, Murai KK, Wang L, Roberts AJ, Pasquale EB, Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport. Proc. Natl. Acad. Sci. U.S.A 106, 12524– 12529 (2009). doi: 10.1073/pnas.0903328106 19592509 PMC2718351 · DOI
- [94]Filosa A. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nat. Neurosci 12, 1285– 1292 (2009). doi: 10.1038/nn.2394 19734893 PMC3922060 · DOI
- [96]Sobel RA, Ephrin A receptors and ligands in lesions and normal-appearing white matter in multiple sclerosis. Brain Pathol. 15, 35– 45 (2005). doi: 10.1111/j.1750-3639.2005.tb00098.x 15779235 PMC8095972 · DOI
- [97]Miranda JD Induction of Eph B3 after spinal cord injury. Exp. Neurol 156, 218– 222 (1999). doi: 10.1006/exnr.1998.7012 10192794 · DOI
- [98]Cissé M. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469, 47– 52 (2011). doi: 10.1038/nature09635 21113149 PMC3030448 · DOI · Paper page
- [99]Nkiliza A. RNA-binding disturbances as a continuum from spinocerebellar ataxia type 2 to Parkinson disease. Neurobiol. Dis 96, 312– 322 (2016). doi: 10.1016/j.nbd.2016.09.014 27663142 · DOI
- [100]Van Hoecke A. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat. Med 18, 1418– 1422 (2012). doi: 10.1038/nm.2901 22922411 · DOI
- [101]Parrinello S. EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting. Cell 143, 145– 155 (2010). doi: 10.1016/j.cell.2010.08.039 20869108 PMC3826531 · DOI
- [104]Sekar A. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177– 183 (2016). doi: 10.1038/nature16549 26814963 PMC4752392 · DOI · Paper page
- [105]Stevens B. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164– 1178(2007). doi: 10.1016/j.cell.2007.10.036 18083105 · DOI · Paper page
- [106]Werneburg S. Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease. Immunity 52, 167– 182.e7 (2020). doi: 10.1016/j.immuni.2019.12.004 31883839 PMC6996144 · DOI · Paper page
- [107]Zhuang Z. EphrinBs regulate D-serine synthesis and release in astrocytes. J. Neurosci 30, 16015– 16024 (2010). doi: 10.1523/JNEUROSCI.0481-10.2010 21106840 PMC3073557 · DOI
- [108]Perez EJ Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury. J. Clin. Invest 127, 3114– 3125 (2017). doi: 10.1172/JCI92300 28714867 PMC5531405 · DOI
- [109]Assis-Nascimento P, Tsenkina Y, Liebl DJ, EphB3 signaling induces cortical endothelial cell death and disrupts the blood-brain barrier after traumatic brain injury. Cell Death Dis. 9, 7 (2018). doi: 10.1038/s41419-017-0016-5 29311672 PMC5849033 · DOI
- [110]Syed YA Antibody-mediated neutralization of myelinassociated EphrinB3 accelerates CNS remyelination. Acta Neuropathol. 131, 281– 298 (2016). doi: 10.1007/s00401-015-1521-1 26687980 PMC4713754 · DOI · Paper page
- [111]Boyd AW, Bartlett PF, Lackmann M, Therapeutic targeting of EPH receptors and their ligands. Nat. Rev. Drug Discov 13, 39– 62 (2014). doi: 10.1038/nrd4175 24378802 · DOI
- [112]Dalva MB EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945– 956 (2000). doi: 10.1016/S0092-8674(00)00197-5 11136979 · DOI
- [113]Takasu MA, Dalva MB, Zigmond RE, Greenberg ME, Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295, 491– 495 (2002). doi: 10.1126/science.1065983 11799243 · DOI
- [114]Tomura M. Monitoring cellular movement in vivo with photoconvertible fluorescence protein “Kaede” transgenic mice. Proc. Natl. Acad. Sci. U.S.A 105, 10871– 10876 (2008). doi: 10.1073/pnas.0802278105 18663225 PMC2504797 · DOI
- [115]Osakada F, Callaway EM, Design and generation of recombinant rabies virus vectors. Nat. Protoc 8, 1583– 1601 (2013). doi: 10.1038/nprot.2013.094 23887178 PMC4028848 · DOI
- [116]Zilionis R. Single-cell barcoding and sequencing using droplet microfluidics. Nat. Protoc 12, 44– 73 (2017). doi: 10.1038/nprot.2016.154 27929523 · DOI
- [117]Klein AM Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell 161, 1187– 1201 (2015). doi: 10.1016/j.cell.2015.04.044 26000487 PMC4441768 · DOI · Paper page
Cited by
Sorted by citations
Function and therapeutic value of astrocytes in neurological diseases
Lee, H.-G., Wheeler, M. A., & Quintana, F. J. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00390-x · Cited by 662 · see citing works
Self-citationWhat is a cell type and how to define it?
Zeng, H. (2022) · Cell · doi:10.1016/j.cell.2022.06.031 · Cited by 439 · see citing works
The immunology of multiple sclerosis
Attfield, K. E., Jensen, L. T., Kaufmann, M., Friese, M. A., & Fugger, L. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-022-00718-z · Cited by 380 · see citing works
Microglia in multiple sclerosis: protectors turn destroyers
Yong, V. W. (2022) · Neuron · doi:10.1016/j.neuron.2022.06.023 · Cited by 185 · see citing works
Hou, J., Zhou, Y., Cai, Z., Terekhova, M., Swain, A., Andhey, P. S., Guimaraes, R. M., Ulezko Antonova, A., Qiu, T., Sviben, S., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112293 · Cited by 85 · see citing works
Feigin, A., Evans, E. E., Fisher, T. L., Leonard, J. E., Smith, E. S., Reader, A., Mishra, V., Manber, R., Walters, K. A., Kowarski, L., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01919-8 · Cited by 67 · see citing works
Chandra, S., Di Meco, A., Dodiya, H. B., Popovic, J., Cuddy, L. K., Weigle, I. Q., Zhang, X., Sadleir, K., Sisodia, S. S., & Vassar, R. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00635-2 · Cited by 58 · see citing works
Huang, Y., Wang, M., Ni, H., Zhang, J., Li, A., Hu, B., Junqueira Alves, C., Wahane, S., Rios de Anda, M., Ho, L., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01664-w · Cited by 42 · see citing works
“A recent study in a mouse model of multiple sclerosis showed that Sema4D expressed by microglia can activate Plexin-B1 and Plexin-B2 expressed in astrocytes 61 .”
Zia, S., Hammond, B. P., Zirngibl, M., Sizov, A., Baaklini, C. S., Panda, S. P., Ho, M. F. S., Lee, K. V., Mainali, A., Burr, M. K., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00584-2 · Cited by 40 · see citing works
Hemonnot-Girard, A.-L., Meersseman, C., Pastore, M., Garcia, V., Linck, N., Rey, C., Chebbi, A., Jeanneteau, F., Ginsberg, S. D., Lachuer, J., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02581-0 · Cited by 24 · see citing works
- Authors
- Clark, I. C., Gutiérrez-Vázquez, C., Wheeler, M. A., Li, Z., Rothhammer, V., Linnerbauer, M., Sanmarco, L. M., Guo, L., Blain, M., Zandee, S. E. J., Chao, C.-C., Batterman, K. V., Schwabenland, M., Lotfy, P., Tejeda-Velarde, A., Hewson, P., Manganeli Polonio, C., Shultis, M. W., Salem, Y., Tjon, E. C., Fonseca-Castro, P. H., Borucki, D. M., Alves de Lima, K., Plasencia, A., Abate, A. R., Rosene, D. L., Hodgetts, K. J., Prinz, M., Antel, J. P., Prat, A., & Quintana, F. J.
- Affiliations
- QB3 (US)
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Montreal Neurological Institute and Hospital (CA)
- Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada.
- Boston University (US)
- University of Freiburg (DE)
- Centre Hospitalier de l’Université de Montréal (CA)
- Corresponding author
- Clark, Iain C.
- Wheeler, Michael A.
- Quintana, Francisco J.
- ORCID
- Clark, Iain C.
- Gutiérrez-Vázquez, Cristina
- Wheeler, Michael A.
- Li, Zhaorong
- Rothhammer, Veit
- Linnerbauer, Mathias
- Sanmarco, Liliana M.
- Guo, Lydia
- Zandee, Stephanie E. J.
- Chao, Chun-Cheih
- Batterman, Katelyn V.
- Schwabenland, Marius
- Lotfy, Peter
- Tejeda-Velarde, Amalia
- Hewson, Patrick
- Manganeli Polonio, Carolina
- Salem, Yasmin
- Fonseca-Castro, Pedro H.
- Borucki, Davis M.
- Alves de Lima, Kalil
- Plasencia, Agustin
- Abate, Adam R.
- Rosene, Douglas L.
- Hodgetts, Kevin J.
- Prinz, Marco
- Antel, Jack P.
- Prat, Alexandre
- Quintana, Francisco J.
- Venue
- Science
- Published
- 2021-04-23
- Volume
- 372
- Issue
- 6540
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC8157482
- OpenAlex
- W3156792714
- Cited by
- 285
- References
- 23
- Citations by year
- 2026: 39 · 2025: 64 · 2024: 51 · 2023: 52 · 2022: 55 · 2021: 24
- FWCI
- 18.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (RG4111A1, JF2161-A-5, 1K99NS114111, F32NS101790, T32CA207201, 5T32AG000222)
- American Cancer Society (PA-1604-08459)
- National Multiple Sclerosis Society (RSG-14-198-01-LIB)
- ASCRS Research Foundation (DFG RO4866 1/1)
- Fonds de Recherche du Québec - Santé (104-2917-I-564)
- Deutsche Forschungsgemeinschaft (CRC/TRR167)
- São Paulo Research Foundation (2019/13731-0, R21AG061678)
- National Cancer Institute, Cairo University (2P30CA006516-48)
- Ministry of Science and Technology, Government of the People’s Republic of Bangladesh (F30AG063463)
- This (NS102807, ES02530, ES029136, AI126880)
- Alfonso Mart Escudero Foundation (ALTF 610-2017)
- Mallinkrodt Pharmaceuticals (A219074)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- astrocyte-microglia interaction, cell-cell interactions, experimental autoimmune encephalomyelitis, multiple sclerosis, axon guidance molecules, Sema4D, ephrin-B3, EphB3, neuroinflammation, pro-inflammatory response
- MeSH terms
- RNA-Seq, Animals, Astrocytes, Brain, Cell Communication, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Humans, Male, Mice, Inbred C57BL, Mitochondria, Multiple Sclerosis, Nerve Tissue Proteins, Herpesvirus 1, Suid, Receptors, Cell Surface, T-Lymphocytes, Signal Transduction, Antigens, CD, NF-kappa B, Reactive Oxygen Species, Microglia, Receptor, EphB3, Ephrin-B3, Semaphorins, Mice, TOR Serine-Threonine Kinases, Single-Cell Analysis
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