Skip to main content

Advertisement

SpringerLink
Log in

Control of autoimmune CNS inflammation by astrocytes

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Multiple sclerosis is a neurologic disease caused by immune cell infiltration into the central nervous system, resulting in gray and white matter inflammation, progressive demyelination, and neuronal loss. Astrocytes, the most abundant cell population in the central nervous system (CNS), have been considered inert scaffold or housekeeping cells for many years. However, recently, it has become clear that this cell population actively modulates the immune response in the CNS at multiple levels. While being exposed to a plethora of cytokines during ongoing autoimmune inflammation, astrocytes modulate local CNS inflammation by secreting cytokines and chemokines, among other factors. This review article gives an overview of the most recent understanding about cytokine networks operational in astrocytes during autoimmune neuroinflammation and highlights potential targets for immunomodulatory therapies for multiple sclerosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Muhlethaler-Mottet A, Di Berardino W, Otten LA, Mach B (1998) Activation of the MHC class II transactivator CIITA by interferon-gamma requires cooperative interaction between Stat1 and USF-1. Immunity 8:157–166

    Article  CAS  PubMed  Google Scholar 

  2. Hashioka S, Klegeris A, Schwab C, Yu S, McGeer PL (2010) Differential expression of interferon-gamma receptor on human glial cells in vivo and in vitro. J Neuroimmunol 225:91–99. doi:10.1016/j.jneuroim.2010.04.023

    Article  CAS  PubMed  Google Scholar 

  3. Nikcevich KM, Gordon KB, Tan L, Hurst SD, Kroepfl JF, Gardinier M, Barrett TA, Miller SD (1997) IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells. J Immunol 158:614–621

    CAS  PubMed  Google Scholar 

  4. Sun D, Coleclough C, Whitaker JN (1997) Nonactivated astrocytes downregulate T cell receptor expression and reduce antigen-specific proliferation and cytokine production of myelin basic protein (MBP)-reactive T cells. J Neuroimmunol 78:69–78

    Article  CAS  PubMed  Google Scholar 

  5. Gold R, Schmied M, Tontsch U, Hartung HP, Wekerle H, Toyka KV, Lassmann H (1996) Antigen presentation by astrocytes primes rat T lymphocytes for apoptotic cell death. A model for T-cell apoptosis in vivo. Brain 119(Pt 2):651–659

    Article  PubMed  Google Scholar 

  6. Yang JF, Tao HQ, Liu YM, Zhan XX, Liu Y, Wang XY, Wang JH, Mu LL, Yang LL, Gao ZM et al (2012) Characterization of the interaction between astrocytes and encephalitogenic lymphocytes during the development of experimental autoimmune encephalitomyelitis (EAE) in mice. Clin Exp Immunol 170:254–265. doi:10.1111/j.1365-2249.2012.04661.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Fitzgerald DC, Zhang G-X, El-Behi M, Fonseca-Kelly Z, Li H, Yu S, Saris CJM, Gran B, Ciric B, Rostami A (2007) Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol 8:1372–1379. doi:10.1038/ni1540

    Article  CAS  PubMed  Google Scholar 

  8. Aloisi F, Ria F, Columba-Cabezas S, Hess H, Penna G, Adorini L (1999) Relative efficiency of microglia, astrocytes, dendritic cells and B cells in naive CD4+ T cell priming and Th1/Th2 cell restimulation. Eur J Immunol 29:2705–2714. doi:10.1002/(SICI)1521-4141(199909)29:09<2705::AID-IMMU2705>3.0.CO;2-1

    Article  CAS  PubMed  Google Scholar 

  9. Sedgwick JD, Mössner R, Schwender S, ter Meulen V (1991) Major histocompatibility complex-expressing nonhematopoietic astroglial cells prime only CD8+ T lymphocytes: astroglial cells as perpetuators but not initiators of CD4+ T cell responses in the central nervous system. J Exp Med 173:1235–1246

    Article  CAS  PubMed  Google Scholar 

  10. Hindinger C, Bergmann CC, Hinton DR, Phares TW, Parra GI, Hussain S, Savarin C, Atkinson RD, Stohlman SA (2012) IFN-γ signaling to astrocytes protects from autoimmune mediated neurological disability. PLoS ONE 7, e42088. doi:10.1371/journal.pone.0042088

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Waisman A, Hauptmann J, Regen T (2015) The role of IL-17 in CNS diseases. Acta Neuropathol 1–13. doi:10.1007/s00401-015-1402-7

  12. Rouvier E, Luciani MF, Mattéi MG, Denizot F, Golstein P (1993) CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus Saimiri gene. J Immunol 150:5445–5456

    CAS  PubMed  Google Scholar 

  13. Sarma Das J, Ciric B, Marek R, Sadhukhan S, Caruso ML, Shafagh J, Fitzgerald DC, Shindler KS, Rostami A (2009) Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. J Neuroinflammation 6:14. doi:10.1186/1742-2094-6-14

    Article  CAS  Google Scholar 

  14. Elain G, Jeanneau K, Rutkowska A, Mir AK, Dev KK (2014) The selective anti-IL17A monoclonal antibody secukinumab (AIN457) attenuates IL17A-induced levels of IL6 in human astrocytes. Glia 62:725–735. doi:10.1002/glia.22637

    Article  PubMed  Google Scholar 

  15. Yi H, Bai Y, Zhu X, Lin L, Zhao L, Wu X, Buch S, Wang L, Chao J, Yao H (2014) IL-17A induces MIP-1α expression in primary astrocytes via Src/MAPK/PI3K/NF-kB pathways: implications for multiple sclerosis. J Neuroimmune Pharmacol 9:629–641. doi:10.1007/s11481-014-9553-1

    Article  PubMed  Google Scholar 

  16. Xiao Y, Jin J, Chang M, Nakaya M, Hu H, Zou Q, Zhou X, Brittain GC, Cheng X, Sun S-C (2014) TPL2 mediates autoimmune inflammation through activation of the TAK1 axis of IL-17 signaling. J Exp Med 211:1689–1702. doi:10.1084/jem.20132640

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Meares GP, Ma X, Qin H, Benveniste EN (2012) Regulation of CCL20 expression in astrocytes by IL-6 and IL-17. Glia 60:771–781. doi:10.1002/glia.22307

    Article  PubMed  Google Scholar 

  18. Liu G, Guo J, Liu J, Wang Z, Liang D (2014) Toll-like receptor signaling directly increases functional IL-17RA expression in neuroglial cells. Clin Immunol 154:127–140. doi:10.1016/j.clim.2014.07.006

    Article  CAS  PubMed  Google Scholar 

  19. Kang Z, Altuntas CZ, Gulen MF, Liu C, Giltiay N, Qin H, Liu L, Qian W, Ransohoff RM, Bergmann C et al (2010) Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32:414–425. doi:10.1016/j.immuni.2010.03.004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Yan Y, Ding X, Li K, Ciric B, Wu S, Xu H, Gran B, Rostami A, Zhang G-X (2012) CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes. Mol Ther 20:1338–1348. doi:10.1038/mt.2012.12

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Kang Z, Wang C, Zepp J, Wu L, Sun K, Zhao J, Chandrasekharan U, DiCorleto PE, Trapp BD, Ransohoff RM et al (2013) Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci 16:1401–1408. doi:10.1038/nn.3505

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Li X (2008) Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling. Cytokine 41:105–113. doi:10.1016/j.cyto.2007.09.015

    Article  CAS  PubMed  Google Scholar 

  23. Wu L, Zepp J, Li X (2012) Function of Act1 in IL-17 family signaling and autoimmunity. Adv Exp Med Biol 946:223–235. doi:10.1007/978-1-4614-0106-3_13

    Article  CAS  PubMed  Google Scholar 

  24. Wang X, Deckert M, Xuan NT, Nishanth G, Just S, Waisman A, Naumann M, Schlüter D (2013) Astrocytic A20 ameliorates experimental autoimmune encephalomyelitis by inhibiting NF-κB- and STAT1-dependent chemokine production in astrocytes. Acta Neuropathol 126:711–724. doi:10.1007/s00401-013-1183-9

    Article  CAS  Google Scholar 

  25. Li Z, Li K, Zhu L, Kan Q, Yan Y, Kumar P, Xu H, Rostami A, Zhang G-X (2013) Inhibitory effect of IL-17 on neural stem cell proliferation and neural cell differentiation. BMC Immunol 14:20. doi:10.1186/1471-2172-14-20

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Heidary M, Rakhshi N, Pahlevan Kakhki M, Behmanesh M, Sanati MH, Sanadgol N, Kamaladini H, Nikravesh A (2014) The analysis of correlation between IL-1B gene expression and genotyping in multiple sclerosis patients. J Neurol Sci 343:41–45. doi:10.1016/j.jns.2014.05.013

    Article  CAS  PubMed  Google Scholar 

  27. Wang Y, Jin S, Sonobe Y, Cheng Y, Horiuchi H, Parajuli B, Kawanokuchi J, Mizuno T, Takeuchi H, Suzumura A (2014) Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes. PLoS ONE 9, e110024. doi:10.1371/journal.pone.0110024

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  28. Ambrosini E, Columba-Cabezas S, Serafini B, Muscella A, Aloisi F (2003) Astrocytes are the major intracerebral source of macrophage inflammatory protein-3alpha/CCL20 in relapsing experimental autoimmune encephalomyelitis and in vitro. Glia 41:290–300. doi:10.1002/glia.10193

    Article  PubMed  Google Scholar 

  29. Argaw AT, Zhang Y, Snyder BJ, Zhao M-L, Kopp N, Lee SC, Raine CS, Brosnan CF, John GR (2006) IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J Immunol 177:5574–5584

    Article  CAS  PubMed  Google Scholar 

  30. Narcisse L, Scemes E, Zhao Y, Lee SC, Brosnan CF (2005) The cytokine IL-1beta transiently enhances P2X7 receptor expression and function in human astrocytes. Glia 49:245–258. doi:10.1002/glia.20110

    Article  PubMed Central  PubMed  Google Scholar 

  31. Mehindate K, Sahlas DJ, Frankel D, Mawal Y, Liberman A, Corcos J, Dion S, Schipper HM (2001) Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis. J Neurochem 77:1386–1395

    Article  CAS  PubMed  Google Scholar 

  32. John GR, Chen L, Rivieccio MA, Melendez-Vasquez CV, Hartley A, Brosnan CF (2004) Interleukin-1beta induces a reactive astroglial phenotype via deactivation of the Rho GTPase-Rock axis. J Neurosci 24:2837–2845. doi:10.1523/JNEUROSCI.4789-03.2004

    Article  CAS  PubMed  Google Scholar 

  33. Li R, Xu W, Chen Y, Qiu W, Shu Y, Wu A, Dai Y, Bao J, Lu Z, Hu X (2014) Raloxifene suppresses experimental autoimmune encephalomyelitis and NF-κB-dependent CCL20 expression in reactive astrocytes. PLoS ONE 9, e94320. doi:10.1371/journal.pone.0094320

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Wu C, Leong SY, Moore CS, Cui Q-L, Gris P, Bernier L-P, Johnson TA, Séguéla P, Kennedy TE, Bar-Or A et al (2013) Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation. J Neuroinflammation 10:41. doi:10.1186/1742-2094-10-41

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Di Penta A, Chiba A, Alloza I, Wyssenbach A, Yamamura T, Villoslada P, Miyake S, Vandenbroeck K (2013) A trifluoromethyl analogue of celecoxib exerts beneficial effects in neuroinflammation. PLoS ONE 8, e83119. doi:10.1371/journal.pone.0083119

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. de Nunes AKS, Rapôso C, de Luna RLA, Cruz-Höfling MAD, Peixoto CA (2012) Sildenafil (Viagra®) down regulates cytokines and prevents demyelination in a cuprizone-induced MS mouse model. Cytokine 60:540–551. doi:10.1016/j.cyto.2012.06.011

    Article  CAS  PubMed  Google Scholar 

  37. Wight RD, Tull CA, Deel MW, Stroope BL, Eubanks AG, Chavis JA, Drew PD, Hensley LL (2012) Resveratrol effects on astrocyte function: relevance to neurodegenerative diseases. Biochem Biophys Res Commun 426:112–115. doi:10.1016/j.bbrc.2012.08.045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Burns SA, Lee Archer R, Chavis JA, Tull CA, Hensley LL, Drew PD (2012) Mitoxantrone repression of astrocyte activation: relevance to multiple sclerosis. Brain Res 1473:236–241. doi:10.1016/j.brainres.2012.07.054

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Wilms H, Sievers J, Rickert U, Rostami-Yazdi M, Mrowietz U, Lucius R (2010) Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation. J Neuroinflammation 7:30. doi:10.1186/1742-2094-7-30

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  40. Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550. doi:10.1146/annurev.immunol.021908.132612

    Article  CAS  PubMed  Google Scholar 

  41. Fukaya T, Someya K, Hibino S, Okada M, Yamane H, Taniguchi K, Yoshimura A (2014) Loss of Sprouty4 in T cells ameliorates experimental autoimmune encephalomyelitis in mice by negatively regulating IL-1β receptor expression. Biochem Biophys Res Commun 447:471–478. doi:10.1016/j.bbrc.2014.04.012

    Article  CAS  PubMed  Google Scholar 

  42. Hirsch JD, Gnanasakthy A, Lale R, Choi K, Sarkin AJ (2014) Efficacy of canakinumab vs. triamcinolone acetonide according to multiple gouty arthritis-related health outcomes measures. Int J Clin Pract 68:1503–1507. doi:10.1111/ijcp.12521

    Article  CAS  PubMed  Google Scholar 

  43. Zager A, Peron JP, Mennecier G, Rodrigues SC, Aloia TP, Palermo-Neto J (2015) Maternal immune activation in late gestation increases neuroinflammation and aggravates experimental autoimmune encephalomyelitis in the offspring. Brain Behav Immun 43:159–171. doi:10.1016/j.bbi.2014.07.021

    Article  CAS  PubMed  Google Scholar 

  44. Bajramović JJ, Bsibsi M, Geutskens SB, Hassankhan R, Verhulst KC, Stege GJ, de Groot CJ, van Noort JM (2000) Differential expression of stress proteins in human adult astrocytes in response to cytokines. J Neuroimmunol 106:14–22

    Article  PubMed  Google Scholar 

  45. Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A (1998) IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol 28:2178–2187. doi:10.1002/(SICI)1521-4141(199807)28:07<2178::AID-IMMU2178>3.0.CO;2-D

    Article  CAS  PubMed  Google Scholar 

  46. Giralt M, Ramos R, Quintana A, Ferrer B, Erta M, Castro-Freire M, Comes G, Sanz E, Unzeta M, Pifarré P et al (2013) Induction of atypical EAE mediated by transgenic production of IL-6 in astrocytes in the absence of systemic IL-6. Glia 61:587–600. doi:10.1002/glia.22457

    Article  PubMed  Google Scholar 

  47. Quintana A, Müller M, Frausto RF, Ramos R, Getts DR, Sanz E, Hofer MJ, Krauthausen M, King NJC, Hidalgo J et al (2009) Site-specific production of IL-6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis. J Immunol 183:2079–2088. doi:10.4049/jimmunol.0900242

    Article  CAS  PubMed  Google Scholar 

  48. Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, Oldstone MB, Mucke L (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A 90:10061–10065

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Middeldorp J, Hol EM (2011) GFAP in health and disease. Prog Neurobiol 93:421–443. doi:10.1016/j.pneurobio.2011.01.005

    Article  CAS  PubMed  Google Scholar 

  50. Haroon F, Drögemüller K, Händel U, Brunn A, Reinhold D, Nishanth G, Mueller W, Trautwein C, Ernst M, Deckert M et al (2011) Gp130-dependent astrocytic survival is critical for the control of autoimmune central nervous system inflammation. J Immunol 186:6521–6531. doi:10.4049/jimmunol.1001135

    Article  CAS  PubMed  Google Scholar 

  51. Smith KJ, Lassmann H (2002) The role of nitric oxide in multiple sclerosis. Lancet Neurol 1:232–241

    Article  CAS  PubMed  Google Scholar 

  52. Liu JS, Zhao ML, Brosnan CF, Lee SC (2001) Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol 158:2057–2066. doi:10.1016/S0002-9440(10)64677-9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Hill KE, Zollinger LV, Watt HE, Carlson NG, Rose JW (2004) Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. J Neuroimmunol 151:171–179. doi:10.1016/j.jneuroim.2004.02.005

    Article  CAS  PubMed  Google Scholar 

  54. Brenner T, Brocke S, Szafer F, Sobel RA, Parkinson JF, Perez DH, Steinman L (1997) Inhibition of nitric oxide synthase for treatment of experimental autoimmune encephalomyelitis. J Immunol 158:2940–2946

    CAS  PubMed  Google Scholar 

  55. Petković F, Blaževski J, Momčilović M, Mostarica Stojkovic M, Miljković D (2013) Nitric oxide inhibits CXCL12 expression in neuroinflammation. Immunol Cell Biol 91:427–434. doi:10.1038/icb.2013.23

    Article  PubMed  CAS  Google Scholar 

  56. Guthikonda P, Baker J, Mattson DH (1998) Interferon-beta-1-b (IFN-B) decreases induced nitric oxide (NO) production by a human astrocytoma cell line. J Neuroimmunol 82:133–139

    Article  CAS  PubMed  Google Scholar 

  57. Wingerchuk DM, Carter JL (2014) Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 89:225–240. doi:10.1016/j.mayocp.2013.11.002

    Article  PubMed  Google Scholar 

  58. Al-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D (2011) Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler 17:939–948. doi:10.1177/1352458511400476

    Article  PubMed  Google Scholar 

  59. Kleinewietfeld M, Hafler DA (2014) Regulatory T cells in autoimmune neuroinflammation. Immunol Rev 259:231–244. doi:10.1111/imr.12169

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Bettini M, Vignali DAA (2009) Regulatory T cells and inhibitory cytokines in autoimmunity. Curr Opin Immunol 21:612–618. doi:10.1016/j.coi.2009.09.011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Heinemann C, Heink S, Petermann F, Vasanthakumar A, Rothhammer V, Doorduijn E, Mitsdoerffer M, Sie C, Prazeres da Costa O, Buch T et al (2014) IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1. Nat Commun 5:3770. doi:10.1038/ncomms4770

    Article  CAS  PubMed  Google Scholar 

  62. Beebe AM, Cua DJ, de Waal Malefyt R (2002) The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Cytokine Growth Factor Rev 13:403–412

    Article  CAS  PubMed  Google Scholar 

  63. Blaževski J, Petković F, Momčilović M, Jevtić B, Miljković D, Mostarica Stojkovic M (2013) High interleukin-10 expression within the central nervous system may be important for initiation of recovery of Dark Agouti rats from experimental autoimmune encephalomyelitis. Immunobiology 218:1192–1199. doi:10.1016/j.imbio.2013.04.004

    Article  PubMed  CAS  Google Scholar 

  64. Molina-Holgado E, Arévalo-Martín A, Castrillo A, Boscá L, Vela JM, Guaza C (2002) Interleukin-4 and interleukin-10 modulate nuclear factor kappaB activity and nitric oxide synthase-2 expression in Theiler’s virus-infected brain astrocytes. J Neurochem 81:1242–1252

    Article  CAS  PubMed  Google Scholar 

  65. Molina-Holgado E, Arévalo-Martín A, Ortiz S, Vela JM, Guaza C (2002) Theiler’s virus infection induces the expression of cyclooxygenase-2 in murine astrocytes: inhibition by the anti-inflammatory cytokines interleukin-4 and interleukin-10. Neurosci Lett 324:237–241

    Article  CAS  PubMed  Google Scholar 

  66. Aharoni R, Kayhan B, Eilam R, Sela M, Arnon R (2003) Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc Natl Acad Sci U S A 100:14157–14162. doi:10.1073/pnas.2336171100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Yang J, Jiang Z, Fitzgerald DC, Ma C, Yu S, Li H, Zhao Z, Li Y, Ciric B, Curtis M et al (2009) Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis. J Clin Invest 119:3678–3691. doi:10.1172/JCI37914

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Mohsenzadegan M, Fayazi MR, Abdolmaleki M, Bakhshayesh M, Seif F, Mousavizadeh K (2015) Direct immunomodulatory influence of IFN-β on human astrocytoma cells. Immunopharmacol Immunotoxicol 37:214–219. doi:10.3109/08923973.2015.1014559

    Article  CAS  PubMed  Google Scholar 

  69. Bsibsi M, Persoon-Deen C, Verwer RWH, Meeuwsen S, Ravid R, van Noort JM (2006) Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 53:688–695. doi:10.1002/glia.20328

    Article  PubMed  Google Scholar 

  70. Li X-L, Lv J, Xi N-N, Wang T, Shang X-F, Xu H-Q, Han Z, O’Byrne KT, Li X-F, Zheng R-Y (2010) Neonatal endotoxin exposure suppresses experimental autoimmune encephalomyelitis through regulating the immune cells responsivity in the central nervous system of adult rats. Biochem Biophys Res Commun 398:302–308. doi:10.1016/j.bbrc.2010.06.086

    Article  CAS  PubMed  Google Scholar 

  71. Cannella B, Raine CS (1995) The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 37:424–435. doi:10.1002/ana.410370404

    Article  CAS  PubMed  Google Scholar 

  72. Cannella B, Raine CS (2004) Multiple sclerosis: cytokine receptors on oligodendrocytes predict innate regulation. Ann Neurol 55:46–57. doi:10.1002/ana.10764

    Article  CAS  PubMed  Google Scholar 

  73. Hulshof S, Montagne L, De Groot CJA, Van Der Valk P (2002) Cellular localization and expression patterns of interleukin-10, interleukin-4, and their receptors in multiple sclerosis lesions. Glia 38:24–35. doi:10.1002/glia.10050

    Article  PubMed  Google Scholar 

  74. Cheng W, Chen G (2014) Chemokines and chemokine receptors in multiple sclerosis. Mediat Inflamm 2014:659206–659208. doi:10.1155/2014/659206

    Google Scholar 

  75. Yoshimura T, Robinson EA, Tanaka S, Appella E, Kuratsu J, Leonard EJ (1989) Purification and amino acid analysis of two human glioma-derived monocyte chemoattractants. J Exp Med 169:1449–1459

    Article  CAS  PubMed  Google Scholar 

  76. Yoshimura T, Yuhki N, Moore SK, Appella E, Lerman MI, Leonard EJ (1989) Human monocyte chemoattractant protein-1 (MCP-1). Full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE. FEBS Lett 244:487–493

    Article  CAS  PubMed  Google Scholar 

  77. O Connor T, Borsig L, Heikenwalder M (2015) CCL2-CCR2 signaling in disease pathogenesis. Endocr Metab Immune Disord Drug Targets

  78. Ransohoff RM, Hamilton TA, Tani M, Stoler MH, Shick HE, Major JA, Estes ML, Thomas DM, Tuohy VK (1993) Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis. FASEB J 7:592–600

    CAS  PubMed  Google Scholar 

  79. Adamus G, Machnicki M, Amundson D, Adlard K, Offner H (1997) Similar pattern of MCP-1 expression in spinal cords and eyes of Lewis rats with experimental autoimmune encephalomyelitis associated anterior uveitis. J Neurosci Res 50:531–538. doi:10.1002/(SICI)1097-4547(19971115)50:4<531::AID-JNR4>3.0.CO;2-F

    Article  CAS  PubMed  Google Scholar 

  80. Shrestha B, Ge S, Pachter JS (2014) Resolution of central nervous system astrocytic and endothelial sources of CCL2 gene expression during evolving neuroinflammation. Fluids Barriers CNS 11:6. doi:10.1186/2045-8118-11-6

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  81. Mayo L, Trauger SA, Blain M, Nadeau M, Patel BN, Alvarez JI, Mascanfroni ID, Yeste A, Kivisakk P, Kallas K et al (2014) Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med. doi:10.1038/nm.3681

    PubMed Central  PubMed  Google Scholar 

  82. Hayashi M, Luo Y, Laning J, Strieter RM, Dorf ME (1995) Production and function of monocyte chemoattractant protein-1 and other beta-chemokines in murine glial cells. J Neuroimmunol 60:143–150

    Article  CAS  PubMed  Google Scholar 

  83. Glabinski AR, Krakowski M, Han Y, Owens T, Ransohoff RM (1999) Chemokine expression in GKO mice (lacking interferon-gamma) with experimental autoimmune encephalomyelitis. J Neurovirol 5:95–101

    Article  CAS  PubMed  Google Scholar 

  84. Giraud SN, Caron CM, Pham-Dinh D, Kitabgi P, Nicot AB (2010) Estradiol inhibits ongoing autoimmune neuroinflammation and NFkappaB-dependent CCL2 expression in reactive astrocytes. Proc Natl Acad Sci 107:8416–8421. doi:10.1073/pnas.0910627107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Kim RY, Hoffman AS, Itoh N, Ao Y, Spence R, Sofroniew MV, Voskuhl RR (2014) Astrocyte CCL2 sustains immune cell infiltration in chronic experimental autoimmune encephalomyelitis. J Neuroimmunol 274:53–61. doi:10.1016/j.jneuroim.2014.06.009

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Paul D, Ge S, Lemire Y, Jellison ER, Serwanski DR, Ruddle NH, Pachter JS (2014) Cell-selective knockout and 3D confocal image analysis reveals separate roles for astrocyte- and endothelial-derived CCL2 in neuroinflammation. J Neuroinflammation 11:10. doi:10.1186/1742-2094-11-10

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  87. Moreno M, Bannerman P, Ma J, Guo F, Miers L, Soulika AM, Pleasure D (2014) Conditional ablation of astroglial CCL2 suppresses CNS accumulation of M1 macrophages and preserves axons in mice with MOG peptide EAE. J Neurosci 34:8175–8185. doi:10.1523/JNEUROSCI.1137-14.2014

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  88. Quinones MP, Kalkonde Y, Estrada CA, Jimenez F, Ramirez R, Mahimainathan L, Mummidi S, Choudhury GG, Martinez H, Adams L et al (2008) Role of astrocytes and chemokine systems in acute TNFalpha induced demyelinating syndrome: CCR2-dependent signals promote astrocyte activation and survival via NF-kappaB and Akt. Mol Cell Neurosci 37:96–109. doi:10.1016/j.mcn.2007.08.017

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Brouwer N, Zuurman MW, Wei T, Ransohoff RM, Boddeke HWGM, Biber K (2004) Induction of glial L-CCR mRNA expression in spinal cord and brain in experimental autoimmune encephalomyelitis. Glia 46:84–94. doi:10.1002/glia.10352

    Article  CAS  PubMed  Google Scholar 

  90. Zuurman MW, Heeroma J, Brouwer N, Boddeke HWGM, Biber K (2003) LPS-induced expression of a novel chemokine receptor (L-CCR) in mouse glial cells in vitro and in vivo. Glia 41:327–336. doi:10.1002/glia.10156

    Article  PubMed  Google Scholar 

  91. Biber K, Zuurman MW, Homan H, Boddeke HWGM (2003) Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8. J Leukoc Biol 74:243–251

    Article  CAS  PubMed  Google Scholar 

  92. Ge S, Shrestha B, Paul D, Keating C, Cone R, Guglielmotti A, Pachter JS (2012) The CCL2 synthesis inhibitor bindarit targets cells of the neurovascular unit, and suppresses experimental autoimmune encephalomyelitis. J Neuroinflammation 9:171. doi:10.1186/1742-2094-9-171

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Guo M-F, Meng J, Li Y-H, Yu J-Z, Liu C-Y, Feng L, Yang W-F, Li J-L, Feng Q-J, Xiao B-G et al (2014) The inhibition of Rho kinase blocks cell migration and accumulation possibly by challenging inflammatory cytokines and chemokines on astrocytes. J Neurol Sci 343:69–75. doi:10.1016/j.jns.2014.05.034

    Article  CAS  PubMed  Google Scholar 

  94. Spence RD, Wisdom AJ, Cao Y, Hill HM, Mongerson CRL, Stapornkul B, Itoh N, Sofroniew MV, Voskuhl RR (2013) Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERα signaling on astrocytes but not through ERβ signaling on astrocytes or neurons. J Neurosci 33:10924–10933. doi:10.1523/JNEUROSCI.0886-13.2013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Utans-Schneitz U, Lorez H, Klinkert WE, da Silva J, Lesslauer W (1998) A novel rat CC chemokine, identified by targeted differential display, is upregulated in brain inflammation. J Neuroimmunol 92:179–190

    Article  CAS  PubMed  Google Scholar 

  96. Varona R, Zaballos A, Gutiérrez J, Martín P, Roncal F, Albar JP, Ardavín C, Márquez G (1998) Molecular cloning, functional characterization and mRNA expression analysis of the murine chemokine receptor CCR6 and its specific ligand MIP-3alpha. FEBS Lett 440:188–194

    Article  CAS  PubMed  Google Scholar 

  97. Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E (2005) Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol 159:12–19. doi:10.1016/j.jneuroim.2004.09.009

    Article  CAS  PubMed  Google Scholar 

  98. Zhou Y, Sonobe Y, Akahori T, Jin S, Kawanokuchi J, Noda M, Iwakura Y, Mizuno T, Suzumura A (2011) IL-9 promotes Th17 cell migration into the central nervous system via CC chemokine ligand-20 produced by astrocytes. J Immunol 186:4415–4421. doi:10.4049/jimmunol.1003307

    Article  CAS  PubMed  Google Scholar 

  99. Liu X, Tian Y, Lu N, Gin T, Cheng CHK, Chan MTV (2013) Stat3 inhibition attenuates mechanical allodynia through transcriptional regulation of chemokine expression in spinal astrocytes. PLoS ONE 8, e75804. doi:10.1371/journal.pone.0075804

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Reboldi A, Reboldi A, Coisne C, Coisne C, Baumjohann D, Baumjohann D, Benvenuto F, Benvenuto F, Bottinelli D, Bottinelli D et al (2009) C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10:514–523. doi:10.1038/ni.1716

    Article  CAS  PubMed  Google Scholar 

  101. van Heteren JT, Rozenberg F, Aronica E, Troost D, Lebon P, Kuijpers TW (2008) Astrocytes produce interferon-alpha and CXCL10, but not IL-6 or CXCL8, in Aicardi-Goutières syndrome. Glia 56:568–578. doi:10.1002/glia.20639

    Article  PubMed  Google Scholar 

  102. Uddin J, Garcia HH, Gilman RH, Gonzalez AE, Friedland JS (2005) Monocyte-astrocyte networks and the regulation of chemokine secretion in neurocysticercosis. J Immunol 175:3273–3281

    Article  CAS  PubMed  Google Scholar 

  103. Zheng JC, Huang Y, Tang K, Cui M, Niemann D, Lopez A, Morgello S, Chen S (2008) HIV-1-infected and/or immune-activated macrophages regulate astrocyte CXCL8 production through IL-1beta and TNF-alpha: involvement of mitogen-activated protein kinases and protein kinase R. J Neuroimmunol 200:100–110. doi:10.1016/j.jneuroim.2008.06.015

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Subileau EA, Rezaie P, Davies HA, Colyer FM, Greenwood J, Male DK, Romero IA (2009) Expression of chemokines and their receptors by human brain endothelium: implications for multiple sclerosis. J Neuropathol Exp Neurol 68:227–240. doi:10.1097/NEN.0b013e318197eca7

    Article  CAS  PubMed  Google Scholar 

  105. Choi SS, Lee HJ, Lim I, Satoh J-I, Kim SU (2014) Human astrocytes: secretome profiles of cytokines and chemokines. PLoS ONE 9, e92325. doi:10.1371/journal.pone.0092325

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  106. Meeuwsen S, Persoon-Deen C, Bsibsi M, Ravid R, van Noort JM (2003) Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli. Glia 43:243–253. doi:10.1002/glia.10259

    Article  PubMed  Google Scholar 

  107. Jing T, Wu L, Borgmann K, Surendran S, Ghorpade A, Liu J, Xiong H (2010) Soluble factors from IL-1β-stimulated astrocytes activate NR1a/NR2B receptors: implications for HIV-1-induced neurodegeneration. Biochem Biophys Res Commun 402:241–246. doi:10.1016/j.bbrc.2010.10.006

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Omari KM, John GR, Sealfon SC, Raine CS (2005) CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis. Brain 128:1003–1015. doi:10.1093/brain/awh479

    Article  PubMed  Google Scholar 

  109. So EY, Kang MH, Kim BS (2006) Induction of chemokine and cytokine genes in astrocytes following infection with Theiler’s murine encephalomyelitis virus is mediated by the Toll-like receptor 3. Glia 53:858–867. doi:10.1002/glia.20346

    Article  PubMed  Google Scholar 

  110. Mohan H, Friese A, Albrecht S, Krumbholz M, Elliott CL, Arthur A, Menon R, Farina C, Junker A, Stadelmann C et al (2014) Transcript profiling of different types of multiple sclerosis lesions yields FGF1 as a promoter of remyelination. Acta Neuropathol Commun 2:178. doi:10.1186/s40478-014-0168-9

    Google Scholar 

  111. Kelland EE, Gilmore W, Weiner LP, Lund BT (2011) The dual role of CXCL8 in human CNS stem cell function: multipotent neural stem cell death and oligodendrocyte progenitor cell chemotaxis. Glia 59:1864–1878. doi:10.1002/glia.21230

    Article  PubMed  Google Scholar 

  112. Khalifa KA, Radwan WM, Attallah KM, Hosney H, Eed EM (2014) Pretreatment serum interferon gamma inducible protein-10 as biomarker of fibrosis and predictor of virological response in genotype 4 hepatitis C virus infection. Acta Gastroenterol Belg 77:401–407

    CAS  PubMed  Google Scholar 

  113. Vazirinejad R, Ahmadi Z, Kazemi Arababadi M, Hassanshahi G, Kennedy D (2014) The biological functions, structure and sources of CXCL10 and its outstanding part in the pathophysiology of multiple sclerosis. Neuroimmunomodulation 21:322–330. doi:10.1159/000357780

    Article  CAS  PubMed  Google Scholar 

  114. Carter SL, Müller M, Manders PM, Campbell IL (2007) Induction of the genes for Cxcl9 and Cxcl10 is dependent on IFN-gamma but shows differential cellular expression in experimental autoimmune encephalomyelitis and by astrocytes and microglia in vitro. Glia 55:1728–1739. doi:10.1002/glia.20587

    Article  PubMed  Google Scholar 

  115. Millward JM, Caruso M, Campbell IL, Gauldie J, Owens T (2007) IFN-gamma-induced chemokines synergize with pertussis toxin to promote T cell entry to the central nervous system. J Immunol 178:8175–8182

    Article  CAS  PubMed  Google Scholar 

  116. Glabinski AR, Tani M, Tuohy VK, Tuthill RJ, Ransohoff RM (1995) Central nervous system chemokine mRNA accumulation follows initial leukocyte entry at the onset of acute murine experimental autoimmune encephalomyelitis. Brain Behav Immun 9:315–330. doi:10.1006/brbi.1995.1030

    Article  CAS  PubMed  Google Scholar 

  117. Rubio N, Arevalo M-A, Cerciat M, Sanz-Rodriguez F, Unkila M, Garcia-Segura LM (2014) Theiler’s virus infection provokes the overexpression of genes coding for the chemokine Ip10 (CXCL10) in SJL/J murine astrocytes, which can be inhibited by modulators of estrogen receptors. J Neurovirol 20:485–495. doi:10.1007/s13365-014-0273-3

    Article  CAS  PubMed  Google Scholar 

  118. Imaizumi T, Numata A, Yano C, Yoshida H, Meng P, Hayakari R, Xing F, Wang L, Matsumiya T, Tanji K et al (2014) ISG54 and ISG56 are induced by TLR3 signaling in U373MG human astrocytoma cells: possible involvement in CXCL10 expression. Neurosci Res 84:34–42. doi:10.1016/j.neures.2014.03.001

    Article  CAS  PubMed  Google Scholar 

  119. Imaizumi T, Murakami K, Ohta K, Seki H, Matsumiya T, Meng P, Hayakari R, Xing F, Aizawa-Yashiro T, Tatsuta T et al (2013) MDA5 and ISG56 mediate CXCL10 expression induced by toll-like receptor 4 activation in U373MG human astrocytoma cells. Neurosci Res 76:195–206. doi:10.1016/j.neures.2013.05.002

    Article  CAS  PubMed  Google Scholar 

  120. Tanuma N, Sakuma H, Sasaki A, Matsumoto Y (2006) Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis. Acta Neuropathol 112:195–204. doi:10.1007/s00401-006-0083-7

    Article  CAS  PubMed  Google Scholar 

  121. Phares TW, Stohlman SA, Hinton DR, Bergmann CC (2013) Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis. J Virol 87:3382–3392. doi:10.1128/JVI.03307-12

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Mills Ko E, Ma JH, Guo F, Miers L, Lee E, Bannerman P, Burns T, Ko D, Sohn J, Soulika AM et al (2014) Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model. J Neuroinflammation 11:105. doi:10.1186/1742-2094-11-105

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  123. Skripuletz T, Hackstette D, Bauer K, Gudi V, Pul R, Voss E, Berger K, Kipp M, Baumgärtner W, Stangel M (2013) Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain 136:147–167. doi:10.1093/brain/aws262

    Article  PubMed  Google Scholar 

  124. Clarner T, Janssen K, Nellessen L, Stangel M, Skripuletz T, Krauspe B, Hess F-M, Denecke B, Beutner C, Linnartz-Gerlach B, et al. (2015) CXCL10 triggers early microglial activation in the cuprizone model. J Immunol 1401459. doi:10.4049/jimmunol.1401459

  125. Moore CS, Cui Q-L, Warsi NM, Durafourt BA, Zorko N, Owen DR, Antel JP, Bar-Or A (2015) Direct and indirect effects of immune and central nervous system-resident cells on human oligodendrocyte progenitor cell differentiation. J Immunol 194:761–772. doi:10.4049/jimmunol.1401156

    Article  CAS  PubMed  Google Scholar 

  126. Sørensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Rottman J, Sellebjerg F, Strieter RM et al (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 103:807–815. doi:10.1172/JCI5150

    Article  PubMed Central  PubMed  Google Scholar 

  127. Sørensen TL, Trebst C, Kivisakk P, Klaege KL, Majmudar A, Ravid R, Lassmann H, Olsen DB, Strieter RM, Ransohoff RM et al (2002) Multiple sclerosis: a study of CXCL10 and CXCR3 co-localization in the inflamed central nervous system. J Neuroimmunol 127:59–68

    Article  PubMed  Google Scholar 

  128. Li M, Ransohoff RM (2008) Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol 84:116–131. doi:10.1016/j.pneurobio.2007.11.003

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Momčilović M, Mostarica Stojkovic M, Miljković D (2012) CXCL12 in control of neuroinflammation. Immunol Res 52:53–63. doi:10.1007/s12026-012-8282-x

    Article  PubMed  CAS  Google Scholar 

  130. McCandless EE, Wang Q, Woerner BM, Harper JM, Klein RS (2006) CXCL12 limits inflammation by localizing mononuclear infiltrates to the perivascular space during experimental autoimmune encephalomyelitis. J Immunol 177:8053–8064

    Article  CAS  PubMed  Google Scholar 

  131. Blaževski J, Petković F, Momčilović M, Jevtić B, Stojković MM, Miljković D (2015) Tumor necrosis factor stimulates expression of CXCL12 in astrocytes. Immunobiology. doi:10.1016/j.imbio.2015.01.007

    PubMed  Google Scholar 

  132. Timotijević G, Petković F, Blaževski J, Momčilović M, Mostarica Stojkovic M, Miljković D (2013) CXCL12-γ expression is inhibited in neuroinflammation. Brain Res 1519:120–126. doi:10.1016/j.brainres.2013.04.056

    Article  PubMed  CAS  Google Scholar 

  133. Meiron M, Zohar Y, Anunu R, Wildbaum G, Karin N (2008) CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells. J Exp Med 205:2643–2655. doi:10.1084/jem.20080730

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  134. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J et al (2001) CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4:702–710. doi:10.1038/89490

    Article  CAS  PubMed  Google Scholar 

  135. Calderon TM, Eugenin EA, Lopez L, Kumar SS, Hesselgesser J, Raine CS, Berman JW (2006) A role for CXCL12 (SDF-1alpha) in the pathogenesis of multiple sclerosis: regulation of CXCL12 expression in astrocytes by soluble myelin basic protein. J Neuroimmunol 177:27–39. doi:10.1016/j.jneuroim.2006.05.003

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Research in the Quintana Laboratory is supported by the National Institutes of Health, the National Multiple Sclerosis Society, the International Progressive MS Alliance, and the American Cancer Society. V. R. received support from Mallinckrodt Pharmaceuticals and the German Research Foundation (DFG, RO4866-1/1).

Author information

Authors and Affiliations

  1. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave. Louis Pasteur, HIM 714, Boston, MA, 02115, USA

    Veit Rothhammer & Francisco J. Quintana

Authors
  1. Veit Rothhammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francisco J. Quintana
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francisco J. Quintana.

Additional information

This article is a contribution to the Special Issue on : Role of Astrocytes and Microglia in CNS Inflammation - Guest Editor: Francisco Quintana

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rothhammer, V., Quintana, F.J. Control of autoimmune CNS inflammation by astrocytes. Semin Immunopathol 37, 625–638 (2015). https://doi.org/10.1007/s00281-015-0515-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-015-0515-3

Keywords

Search

Navigation