Skip to main content

Advertisement

SpringerLink
Log in

Immune Players in the CNS: The Astrocyte

  • INVITED REVIEW
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

In the finely balanced environment of the central nervous system astrocytes, the most numerous cell type, play a role in regulating almost every physiological system. First found to regulate extracellular ions and pH, they have since been shown to regulate neurotransmitter levels, cerebral blood flow and energy metabolism. There is also growing evidence for an essential role of astrocytes in central immunity, which is the topic of this review. In the healthy state, the central nervous system is potently anti-inflammatory but under threat astrocytes readily respond to pathogens and to both sterile and pathogen-induced cell damage. In response, astrocytes take on some of the roles of immune cells, releasing cyto- and chemokines to influence effector cells, modulating the blood–brain barrier and forming glial scars. To date, much of the data supporting a role for astrocytes in immunity have been obtained from in vitro systems; however data from experimental models and clinical samples support the suggestion that astrocytes perform similar roles in more complex environments. This review will discuss some aspects of the role of astrocytes in central nervous system immunity.

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

Similar content being viewed by others

References

  • Aloisi F, Penna G, Cerase J, Menendez Iglesias B, Adorini L (1997) IL-12 production by central nervous system microglia is inhibited by astrocytes. J Immunol 159:1604–1612

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Alter A, Duddy M, Hebert S, Biernacki K, Prat A, Antel JP, Yong VW, Nuttall RK, Pennington CJ, Edwards DR, Bar-Or A (2003) Determinants of human B cell migration across brain endothelial cells. J Immunol 170:4497–4505

    CAS  PubMed  Google Scholar 

  • An Y, Chen Q, Quan N (2011) Interleukin-1 exerts distinct actions on different cell types of the brain in vitro. J Inflamm Res 2011:11–20

    PubMed  Google Scholar 

  • Andersson A, Covacu R, Sunnemark D, Danilov AI, Dal Bianco A, Khademi M, Wallstrom E, Lobell A, Brundin L, Lassmann H, Harris RA (2008) Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J Leukoc Biol 84:1248–1255

    Article  CAS  PubMed  Google Scholar 

  • Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, Mariani JN, Mahase S, Dutta DJ, Seto J, Kramer EG, Ferrara N, Sofroniew MV, John GR (2012) Astrocyte-derived VEGF-A drives blood–brain barrier disruption in CNS inflammatory disease. J Clin Invest 122:2454–2468

    Article  CAS  PubMed  Google Scholar 

  • Bachoo RM, Kim RS, Ligon KL, Maher EA, Brennan C, Billings N, Chan S, Li C, Rowitch DH, Wong WH, DePinho RA (2004) Molecular diversity of astrocytes with implications for neurological disorders. Proc Natl Acad Sci USA 101:8384–8389

    Article  CAS  PubMed  Google Scholar 

  • Ballestas ME, Benveniste EN (1997) Elevation of cyclic AMP levels in astrocytes antagonizes cytokine-induced adhesion molecule expression. J Neurochem 69:1438–1448

    Article  CAS  PubMed  Google Scholar 

  • Bechmann I, Galea I, Perry VH (2007) What is the blood–brain barrier (not)? Trends Immunol 28:5–11

    Article  CAS  PubMed  Google Scholar 

  • Benveniste EN, Tang LP, Law RM (1995) Differential regulation of astrocyte TNF-alpha expression by the cytokines TGF-beta, IL-6 and IL-10. Int J Dev Neurosci 13:341–349

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Brenneman DE, Hauser J, Spong CY, Phillips TM (2000) Chemokines released from astroglia by vasoactive intestinal peptide. Mechanism of neuroprotection from HIV envelope protein toxicity. Ann N Y Acad Sci 921:109–114

    Article  CAS  PubMed  Google Scholar 

  • Brenneman DE, Phillips TM, Hauser J, Hill JM, Spong CY, Gozes I (2003) Complex array of cytokines released by vasoactive intestinal peptide. Neuropeptides 37:111–119

    Article  CAS  PubMed  Google Scholar 

  • Brosnan CF, Cannella B, Battistini L, Raine CS (1995) Cytokine localization in multiple sclerosis lesions: correlation with adhesion molecule expression and reactive nitrogen species. Neurology 45:S16–S21

    Article  CAS  PubMed  Google Scholar 

  • Brown AM, Ransom BR (2007) Astrocyte glycogen and brain energy metabolism. Glia 55:1263–1271

    Article  PubMed  Google Scholar 

  • Bsibsi M, Ravid R, Gveric D, van Noort JM (2002) Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61:1013–1021

    CAS  PubMed  Google Scholar 

  • Bsibsi M, Persoon-Deen C, Verwer RW, 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

    Article  PubMed  Google Scholar 

  • 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

  • Burudi EM, Regnier-Vigouroux A (2001) Regional and cellular expression of the mannose receptor in the post-natal developing mouse brain. Cell Tissue Res 303:307–317

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 USA 90:10061–10065

    Article  CAS  PubMed  Google Scholar 

  • Carpentier PA, Begolka WS, Olson JK, Elhofy A, Karpus WJ, Miller SD (2005) Differential activation of astrocytes by innate and adaptive immune stimuli. Glia 49:360–374

    Article  PubMed  Google Scholar 

  • Chaboub LS, Deneen B (2012) Developmental origins of astrocyte heterogeneity: the final frontier of CNS development. Dev Neurosci 34:379–388

    Article  CAS  PubMed  Google Scholar 

  • Chan WY, Kohsaka S, Rezaie P (2007) The origin and cell lineage of microglia: new concepts. Brain Res Rev 53:344–354

    Article  CAS  PubMed  Google Scholar 

  • Chastain EM, Duncan DS, Rodgers JM, Miller SD (2010) The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 1812:265–274

    PubMed  Google Scholar 

  • Chauhan VS, Furr SR, Grdzelishvili VZ, Marriott I (2009a) Primary human astrocytes functionally express RIG-I, a member of the retinoic acid-inducible gene-I family of viral pattern recognition receptors. J Immunol 182(Meeting Abstract Supplement):133–148

    Google Scholar 

  • Chauhan VS, Sterka DG Jr, Furr SR, Young AB, Marriott I (2009b) NOD2 plays an important role in the inflammatory responses of microglia and astrocytes to bacterial CNS pathogens. Glia 57:414–423

    Article  PubMed  Google Scholar 

  • Choi SJ, Lee KH, Park HS, Kim SK, Koh CM, Park JY (2005) Differential expression, shedding, cytokine regulation and function of TNFR1 and TNFR2 in human fetal astrocytes. Yonsei Med J 46:818–826

    Article  CAS  PubMed  Google Scholar 

  • Chung IY, Benveniste EN (1990) Tumor necrosis factor-alpha production by astrocytes. Induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. J Immunol 144:2999–3007

    CAS  PubMed  Google Scholar 

  • Colodner KJ, Montana RA, Anthony DC, Folkerth RD, De Girolami U, Feany MB (2005) Proliferative potential of human astrocytes. J Neuropathol Exp Neurol 64:163–169

    PubMed  Google Scholar 

  • Constantinescu CS, Tani M, Ransohoff RM, Wysocka M, Hilliard B, Fujioka T, Murphy S, Tighe PJ, Das Sarma J, Trinchieri G, Rostami A (2005) Astrocytes as antigen-presenting cells: expression of IL-12/IL-23. J Neurochem 95:331–340

    Article  CAS  PubMed  Google Scholar 

  • Croitoru-Lamoury J, Guillemin GJ, Boussin FD, Mognetti B, Gigout LI, Cheret A, Vaslin B, Le Grand R, Brew BJ, Dormont D (2003) Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation. Glia 41:354–370

    Article  PubMed  Google Scholar 

  • Cross AH, Ku G (2000) Astrocytes and central nervous system endothelial cells do not express B7-1 (CD80) or B7-2 (CD86) immunoreactivity during experimental autoimmune encephalomyelitis. J Neuroimmunol 110:76–82

    Article  CAS  PubMed  Google Scholar 

  • D’Agostino PM, Gottfried-Blackmore A, Anandasabapathy N, Bulloch K (2012) Brain dendritic cells: biology and pathology. Acta Neuropathol

  • De Keyser J, Wilczak N, Leta R, Streetland C (1999) Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors. Neurology 53:1628–1633

    Article  PubMed  Google Scholar 

  • De Miranda J, Yaddanapudi K, Hornig M, Lipkin WI (2009) Astrocytes recognize intracellular polyinosinic-polycytidylic acid via MDA-5. FASEB J 23:1064–1071

    Article  PubMed  CAS  Google Scholar 

  • Deiva K, Khiati A, Hery C, Salim H, Leclerc P, Horellou P, Tardieu M (2006) CCR5-, DC-SIGN-dependent endocytosis and delayed reverse transcription after human immunodeficiency virus type 1 infection in human astrocytes. AIDS Res Hum Retroviruses 22:1152–1161

    Article  CAS  PubMed  Google Scholar 

  • Dinarello CA (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117:3720–3732

    Article  CAS  PubMed  Google Scholar 

  • Drickamer K (1999) C-type lectin-like domains. Curr Opin Struct Biol 9:585–590

    Article  CAS  PubMed  Google Scholar 

  • Durrenberger PF, Ettorre A, Kamel F, Webb LV, Sim M, Nicholas RS, Malik O, Reynolds R, Boyton RJ, Altmann DM (2012) Innate immunity in multiple sclerosis white matter lesions: expression of natural cytotoxicity triggering receptor 1 (NCR1). J Neuroinflammation 9:1

    Article  CAS  PubMed  Google Scholar 

  • Emsley JG, Macklis JD (2006) Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol 2:175–186

    Article  PubMed  Google Scholar 

  • Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Fattori E, Lazzaro D, Musiani P, Modesti A, Alonzi T, Ciliberto G (1995) IL-6 expression in neurons of transgenic mice causes reactive astrocytosis and increase in ramified microglial cells but no neuronal damage. Eur J Neurosci 7:2441–2449

    Article  CAS  PubMed  Google Scholar 

  • Frohman EM, Vayuvegula B, Gupta S, van den Noort S (1988a) Norepinephrine inhibits gamma-interferon-induced major histocompatibility class II (Ia) antigen expression on cultured astrocytes via beta-2-adrenergic signal transduction mechanisms. Proc Natl Acad Sci USA 85:1292–1296

    Article  CAS  PubMed  Google Scholar 

  • Frohman EM, Frohman TC, Vayuvegula B, Gupta S, van den Noort S (1988b) Vasoactive intestinal polypeptide inhibits the expression of the MHC class II antigens on astrocytes. J Neurol Sci 88:339–346

    Article  CAS  PubMed  Google Scholar 

  • Furr SR, Chauhan VS, Sterka D Jr, Grdzelishvili V, Marriott I (2008) Characterization of retinoic acid-inducible gene-I expression in primary murine glia following exposure to vesicular stomatitis virus. J Neurovirol 14:503–513

    Article  CAS  PubMed  Google Scholar 

  • Furr SR, Chauhan VS, Moerdyk-Schauwecker MJ, Marriott I (2011) A role for DNA-dependent activator of interferon regulatory factor in the recognition of herpes simplex virus type 1 by glial cells. J Neuroinflammation 8:99

    Article  CAS  PubMed  Google Scholar 

  • Ge S, Murugesan N, Pachter JS (2009) Astrocyte- and endothelial-targeted CCL2 conditional knockout mice: critical tools for studying the pathogenesis of neuroinflammation. J Mol Neurosci 39:269–283

    Article  CAS  PubMed  Google Scholar 

  • Geijtenbeek TB, Gringhuis SI (2009) Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol 9:465–479

    Article  CAS  PubMed  Google Scholar 

  • Geurts JJ, Wolswijk G, Bo L, van der Valk P, Polman CH, Troost D, Aronica E (2003) Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis. Brain 126:1755–1766

    Article  CAS  PubMed  Google Scholar 

  • Geurts JJ, Wolswijk G, Bo L, Redeker S, Ramkema M, Troost D, Aronica E (2005) Expression patterns of Group III metabotropic glutamate receptors mGluR4 and mGluR8 in multiple sclerosis lesions. J Neuroimmunol 158:182–190

    Article  CAS  PubMed  Google Scholar 

  • Gimenez MA, Sim JE, Russell JH (2004) TNFR1-dependent VCAM-1 expression by astrocytes exposes the CNS to destructive inflammation. J Neuroimmunol 151:116–125

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Gorina R, Font-Nieves M, Marquez-Kisinousky L, Santalucia T, Planas AM (2010) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59:242–255

    Article  Google Scholar 

  • Goursaud S, Kozlova EN, Maloteaux JM, Hermans E (2009) Cultured astrocytes derived from corpus callosum or cortical grey matter show distinct glutamate handling properties. J Neurochem 108:1442–1452

    Article  CAS  PubMed  Google Scholar 

  • Halassa MM, Fellin T, Haydon PG (2007a) The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med 13:54–63

    Article  CAS  PubMed  Google Scholar 

  • Halassa MM, Fellin T, Takano H, Dong JH, Haydon PG (2007b) Synaptic islands defined by the territory of a single astrocyte. J Neurosci 27:6473–6477

    Article  CAS  PubMed  Google Scholar 

  • Hayashi Y, Nomura M, Yamagishi S, Harada S, Yamashita J, Yamamoto H (1997) Induction of various blood–brain barrier properties in non-neural endothelial cells by close apposition to co-cultured astrocytes. Glia 19:13–26

    Article  CAS  PubMed  Google Scholar 

  • Hellendall RP, Ting JP (1997) Differential regulation of cytokine-induced major histocompatibility complex class II expression and nitric oxide release in rat microglia and astrocytes by effectors of tyrosine kinase, protein kinase C, and cAMP. J Neuroimmunol 74:19–29

    Article  CAS  PubMed  Google Scholar 

  • Huang D, Wujek J, Kidd G, He TT, Cardona A, Sasse ME, Stein EJ, Kish J, Tani M, Charo IF, Proudfoot AE, Rollins BJ, Handel T, Ransohoff RM (2005) Chronic expression of monocyte chemoattractant protein-1 in the central nervous system causes delayed encephalopathy and impaired microglial function in mice. FASEB J 19:761–772

    Article  CAS  PubMed  Google Scholar 

  • Imeri L, Opp MR (2009) How (and why) the immune system makes us sleep. Nat Rev Neurosci 10:199–210

    Article  CAS  PubMed  Google Scholar 

  • Issazadeh S, Navikas V, Schaub M, Sayegh M, Khoury S (1998) Kinetics of expression of costimulatory molecules and their ligands in murine relapsing experimental autoimmune encephalomyelitis in vivo. J Immunol 161:1104–1112

    CAS  PubMed  Google Scholar 

  • Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, Shapiro A, Antel JP (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175:4320–4330

    CAS  PubMed  Google Scholar 

  • Jelinek I, Leonard JN, Price GE, Brown KN, Meyer-Manlapat A, Goldsmith PK, Wang Y, Venzon D, Epstein SL, Segal DM (2011) TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection. J Immunol 186:2422–2429

    Article  CAS  PubMed  Google Scholar 

  • Jiang G, Sun D, Kaplan HJ, Shao H (2012) Retinal astrocytes pretreated with NOD2 and TLR2 ligands activate uveitogenic T cells. PLoS One 7:e40510

    Article  CAS  PubMed  Google Scholar 

  • Kang Z, Altuntas CZ, Gulen MF, Liu C, Giltiay N, Qin H, Liu L, Qian W, Ransohoff RM, Bergmann C, Stohlman S, Tuohy VK, Li X (2010) Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32:414–425

    Article  CAS  PubMed  Google Scholar 

  • Kawanokuchi J, Mizuno T, Takeuchi H, Kato H, Wang J, Mitsuma N, Suzumura A (2006) Production of interferon-gamma by microglia. Mult Scler 12:558–564

    Article  CAS  PubMed  Google Scholar 

  • Kim JB, Sig Choi J, Yu YM, Nam K, Piao CS, Kim SW, Lee MH, Han PL, Park JS, Lee JK (2006) HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26:6413–6421

    Article  CAS  PubMed  Google Scholar 

  • Kim H, Yang E, Lee J, Kim SH, Shin JS, Park JY, Choi SJ, Kim SJ, Choi IH (2008) Double-stranded RNA mediates interferon regulatory factor 3 activation and interleukin-6 production by engaging Toll-like receptor 3 in human brain astrocytes. Immunology 124:480–488

    Article  CAS  PubMed  Google Scholar 

  • Koehler RC, Roman RJ, Harder DR (2009) Astrocytes and the regulation of cerebral blood flow. Trends Neurosci 32:160–169

    Article  CAS  PubMed  Google Scholar 

  • Kostianovsky AM, Maier LM, Anderson RC, Bruce JN, Anderson DE (2008) Astrocytic regulation of human monocytic/microglial activation. J Immunol 181:5425–5432

    CAS  PubMed  Google Scholar 

  • Lee SC, Collins M, Vanguri P, Shin ML (1992) Glutamate differentially inhibits the expression of class-II MHC antigens on astrocytes and microglia. J Immunol 148:3391–3397

    CAS  PubMed  Google Scholar 

  • Lee SC, Liu W, Dickson DW, Brosnan CF, Berman JW (1993) Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J Immunol 150:2659–2667

    CAS  PubMed  Google Scholar 

  • Lukaszevicz AC, Sampaio N, Guegan C, Benchoua A, Couriaud C, Chevalier E, Sola B, Lacombe P, Onteniente B (2002) High sensitivity of protoplasmic cortical astroglia to focal ischemia. J Cereb Blood Flow Metab 22:289–298

    Article  CAS  PubMed  Google Scholar 

  • Luo Y, Berman MA, Zhai Q, Fischer FR, Abromson-Leeman SR, Zhang Y, Kuziel WA, Gerard C, Dorf ME (2002) RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytes. Glia 39:19–30

    Article  PubMed  Google Scholar 

  • Ma X, Reynolds SL, Baker BJ, Li X, Benveniste EN, Qin H (2010) IL-17 enhancement of the IL-6 signaling cascade in astrocytes. J Immunol 184:4898–4906

    Article  CAS  PubMed  Google Scholar 

  • Magalhaes JG, Fritz JH, Le Bourhis L, Sellge G, Travassos LH, Selvanantham T, Girardin SE, Gommerman JL, Philpott DJ (2008) Nod2-dependent Th2 polarization of antigen-specific immunity. J Immunol 181:7925–7935

    CAS  PubMed  Google Scholar 

  • Manni M, Granstein RD, Maestroni G (2011) beta2-Adrenergic agonists bias TLR-2 and NOD2 activated dendritic cells towards inducing an IL-17 immune response. Cytokine 55:380–386

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto M, Funami K, Tanabe M, Oshiumi H, Shingai M, Seto Y, Yamamoto A, Seya T (2003) Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol 171:3154–3162

    CAS  PubMed  Google Scholar 

  • Matsushita T, Tateishi T, Isobe N, Yonekawa T, Yamasaki R, Matsuse D, Murai H, Kira J (2013) Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis. PLoS One 8:e61835

    Article  CAS  PubMed  Google Scholar 

  • McKimmie CS, Fazakerley JK (2005) In response to pathogens, glial cells dynamically and differentially regulate Toll-like receptor gene expression. J Neuroimmunol 169:116–125

    Article  CAS  PubMed  Google Scholar 

  • McKimmie CS, Graham GJ (2010) Astrocytes modulate the chemokine network in a pathogen-specific manner. Biochem Biophys Res Commun 394:1006–1011

    Article  CAS  PubMed  Google Scholar 

  • McNamee EN, Ryan KM, Griffin EW, Gonzalez-Reyes RE, Ryan KJ, Harkin A, Connor TJ (2010) Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: Implications for neurodegeneration. Brain Behav Immun 24:660–671

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Meinl E, Aloisi F, Ertl B, Weber F, de Waal MR, Wekerle H, Hohlfeld R (1994) Multiple sclerosis. Immunomodulatory effects of human astrocytes on T cells. Brain 117(Pt 6):1323–1332

    Article  PubMed  Google Scholar 

  • Moreno M, Guo F, Ko EM, Bannerman P, Soulika A, Pleasure D (2013) Origins and significance of astrogliosis in the multiple sclerosis model, MOG peptide EAE. J Neurol Sci

  • Morga E, Faber C, Heuschling P (2000) Stimulation of endothelin B receptor modulates the inflammatory activation of rat astrocytes. J Neurochem 74:603–612

    Article  CAS  PubMed  Google Scholar 

  • Morga E, Mouad-Amazzal L, Felten P, Heurtaux T, Moro M, Michelucci A, Gabel S, Grandbarbe L, Heuschling P (2009) Jagged1 regulates the activation of astrocytes via modulation of NFkappaB and JAK/STAT/SOCS pathways. Glia 57:1741–1753

    Article  PubMed  Google Scholar 

  • Myers KJ, Dougherty JP, Ron Y (1993) In vivo antigen presentation by both brain parenchymal cells and hematopoietically derived cells during the induction of experimental autoimmune encephalomyelitis. J Immunol 151:2252–2260

    CAS  PubMed  Google Scholar 

  • Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Nikcevich KM, Piskurich JF, Hellendall RP, Wang Y, Ting JPY (1999) Differential selectivity of CIITA promoter activation by IFN-[gamma] and IRF-1 in astrocytes and macrophages: CIITA promoter activation is not affected by TNF-[alpha]. J Neuroimmunol 99:195–204

    Article  CAS  PubMed  Google Scholar 

  • O’Keefe GM, Nguyen VT, Benveniste EN (1999) Class II transactivator and class II MHC gene expression in microglia: modulation by the cytokines TGF-beta, IL-4, IL-13 and IL-10. Eur J Immunol 29:1275–1285

    Article  PubMed  Google Scholar 

  • Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29:547–553

    Article  CAS  PubMed  Google Scholar 

  • Ogata K, Kosaka T (2002) Structural and quantitative analysis of astrocytes in the mouse hippocampus. Neuroscience 113:221–233

    Article  CAS  PubMed  Google Scholar 

  • Oh JW, Van Wagoner NJ, Rose-John S, Benveniste EN (1998) Role of IL-6 and the soluble IL-6 receptor in inhibition of VCAM-1 gene expression. J Immunol 161:4992–4999

    CAS  PubMed  Google Scholar 

  • Ousman SS, Kubes P (2012) Immune surveillance in the central nervous system. Nat Neurosci 15:1096–1101

    Article  CAS  PubMed  Google Scholar 

  • Pagenstecher A, Lassmann S, Carson MJ, Kincaid CL, Stalder AK, Campbell IL (2000) Astrocyte-targeted expression of IL-12 induces active cellular immune responses in the central nervous system and modulates experimental allergic encephalomyelitis. J Immunol 164:4481–4492

    CAS  PubMed  Google Scholar 

  • Park C, Lee S, Cho IH, Lee HK, Kim D, Choi SY, Oh SB, Park K, Kim JS, Lee SJ (2006) TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. Glia 53:248–256

    Article  PubMed  Google Scholar 

  • Pedrazzi M, Patrone M, Passalacqua M, Ranzato E, Colamassaro D, Sparatore B, Pontremoli S, Melloni E (2007) Selective proinflammatory activation of astrocytes by high-mobility group box 1 protein signaling. J Immunol 179:8525–8532

    CAS  PubMed  Google Scholar 

  • Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–431

    Article  CAS  PubMed  Google Scholar 

  • Pereira A Jr, Furlan FA (2010) Astrocytes and human cognition: modeling information integration and modulation of neuronal activity. Prog Neurobiol 92:405–420

    Article  PubMed  Google Scholar 

  • Peters A, Palay S, Webster H (1991) The fine structure of the nervous system, Thirdth edn. Oxford University Press, New York

    Google Scholar 

  • Pratt BM, McPherson JM (1997) TGF-beta in the central nervous system: potential roles in ischemic injury and neurodegenerative diseases. Cytokine Growth Factor Rev 8:267–292

    Article  CAS  PubMed  Google Scholar 

  • Proell M, Riedl SJ, Fritz JH, Rojas AM, Schwarzenbacher R (2008) The Nod-like receptor (NLR) family: a tale of similarities and differences. PLoS One 3:e2119

    Article  PubMed  CAS  Google Scholar 

  • Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, Salomone S, Moskowitz MA (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28:927–938

    Article  CAS  PubMed  Google Scholar 

  • Quintana A, Erta M, Ferrer B, Comes G, Giralt M, Hidalgo J (2012) Astrocyte-specific deficiency of interleukin-6 and its receptor reveal specific roles in survival, body weight and behavior. Brain Behav Immun

  • 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 

  • Reier PJ, Houle JD (1988) The glial scar: its bearing on axonal elongation and transplantation approaches to CNS repair. Adv Neurol 47:87–138

    CAS  PubMed  Google Scholar 

  • Rivieccio MA, Suh H-S, Zhao Y, Zhao M-L, Chin KC, Lee SC, Brosnan CF (2006) TLR3 ligation activates an antiviral response in human fetal astrocytes: a role for Viperin/cig5. J Immunol 177:4735–4741

    CAS  PubMed  Google Scholar 

  • Saad B, Constam DB, Ortmann R, Moos M, Fontana A, Schachner M (1991) Astrocyte-derived TGF-beta 2 and NGF differentially regulate neural recognition molecule expression by cultured astrocytes. J Cell Biol 115:473–484

    Article  CAS  PubMed  Google Scholar 

  • Saikali P, Antel JP, Pittet CL, Newcombe J, Arbour N (2010) Contribution of astrocyte-derived IL-15 to CD8 T cell effector functions in multiple sclerosis. J Immunol 185:5693–5703

    Article  CAS  PubMed  Google Scholar 

  • Santello M, Volterra A (2012) TNFalpha in synaptic function: switching gears. Trends Neurosci 35:638–647

    Article  CAS  PubMed  Google Scholar 

  • Santello M, Bezzi P, Volterra A (2011) TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69:988–1001

    Article  CAS  PubMed  Google Scholar 

  • Santello M, Cali C, Bezzi P (2012) Gliotransmission and the tripartite synapse. Adv Exp Med Biol 970:307–331

    Article  CAS  PubMed  Google Scholar 

  • Savarin C, Stohlman SA, Rietsch AM, Butchi N, Ransohoff RM, Bergmann CC (2011) MMP9 deficiency does not decrease blood–brain barrier disruption, but increases astrocyte MMP3 expression during viral encephalomyelitis. Glia 59:1770–1781

    Article  PubMed  Google Scholar 

  • Schweitzer AN, Sharpe AH (1998) Studies using antigen-presenting cells lacking expression of both B7-1 (CD80) and B7-2 (CD86) show distinct requirements for B7 molecules during priming versus restimulation of Th2 but not Th1 cytokine production. J Immunol 161:2762–2771

    CAS  PubMed  Google Scholar 

  • Scumpia PO, Kelly KM, Reeves WH, Stevens BR (2005) Double-stranded RNA signals antiviral and inflammatory programs and dysfunctional glutamate transport in TLR3-expressing astrocytes. Glia 52:153–162

    Article  PubMed  Google Scholar 

  • Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI, Goodman M, Redmond JC, Bonar CJ, Erwin JM, Hof PR (2006) Evolution of increased glia-neuron ratios in the human frontal cortex. Proc Natl Acad Sci USA 103:13606–13611

    Article  CAS  PubMed  Google Scholar 

  • Shrikant P, Weber E, Jilling T, Benveniste EN (1995) Intercellular adhesion molecule-1 gene expression by glial cells. Differential mechanisms of inhibition by IL-10 and IL-6. J Immunol 155:1489–1501

    CAS  PubMed  Google Scholar 

  • Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35

    Article  PubMed  Google Scholar 

  • Soos JM, Ashley TA, Morrow J, Patarroyo JC, Szente BE, Zamvil SS (1999) Differential expression of B7 co-stimulatory molecules by astrocytes correlates with T cell activation and cytokine production. Int Immunol 11:1169–1179

    Article  CAS  PubMed  Google Scholar 

  • Spacek J (1985) Three-dimensional analysis of dendritic spines. III. Glial sheath. Anat Embryol (Berl) 171:245–252

    Article  CAS  Google Scholar 

  • Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, Gerlo S (2011) Interleukin-6, a mental cytokine. Brain Res Rev 67:157–183

    Article  CAS  PubMed  Google Scholar 

  • Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440:1054–1059

    Article  CAS  PubMed  Google Scholar 

  • Sterka D Jr, Rati DM, Marriott I (2006) Functional expression of NOD2, a novel pattern recognition receptor for bacterial motifs, in primary murine astrocytes. Glia 53:322–330

    Article  PubMed  Google Scholar 

  • Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178

    Article  CAS  PubMed  Google Scholar 

  • Sulkowski G, Dabrowska-Bouta B, Kwiatkowska-Patzer B, Struzynska L (2009) Alterations in glutamate transport and group I metabotropic glutamate receptors in the rat brain during acute phase of experimental autoimmune encephalomyelitis. Folia Neuropathol 47:329–337

    CAS  PubMed  Google Scholar 

  • Sunnemark D, Eltayeb S, Nilsson M, Wallstrom E, Lassmann H, Olsson T, Berg AL, Ericsson-Dahlstrand A (2005) CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin. J Neuroinflammation 2:17

    Article  PubMed  CAS  Google Scholar 

  • Tan L, Gordon KB, Mueller JP, Matis LA, Miller SD (1998) Presentation of proteolipid protein epitopes and B7-1-dependent activation of encephalitogenic T cells by IFN-gamma-activated SJL/J astrocytes. J Immunol 160:4271–4279

    CAS  PubMed  Google Scholar 

  • Tanaka M, Shih PY, Gomi H, Yoshida T, Nakai J, Ando R, Furuichi T, Mikoshiba K, Semyanov A, Itohara S (2013) Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol Brain 6:6

    Article  CAS  PubMed  Google Scholar 

  • Tisell A, Leinhard OD, Warntjes JB, Aalto A, Smedby O, Landtblom AM, Lundberg P (2013) Increased concentrations of glutamate and glutamine in normal-appearing white matter of patients with multiple sclerosis and normal MR imaging brain scans. PLoS One 8:e61817

    Article  CAS  PubMed  Google Scholar 

  • Trajkovic V, Vuckovic O, Stosic-Grujicic S, Miljkovic D, Popadic D, Markovic M, Bumbasirevic V, Backovic A, Cvetkovic I, Harhaji L, Ramic Z, Mostarica Stojkovic M (2004) Astrocyte-induced regulatory T cells mitigate CNS autoimmunity. Glia 47:168–179

    Article  PubMed  Google Scholar 

  • Traugott U, Scheinberg LC, Raine CS (1985) On the presence of Ia-positive endothelial cells and astrocytes in multiple sclerosis lesions and its relevance to antigen presentation. J Neuroimmunol 8:1–14

    Article  CAS  PubMed  Google Scholar 

  • Tubridy N, Behan PO, Capildeo R, Chaudhuri A, Forbes R, Hawkins CP, Hughes RA, Palace J, Sharrack B, Swingler R, Young C, Moseley IF, MacManus DG, Donoghue S, Miller DH (1999) The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group. Neurology 53:466–472

    Article  CAS  PubMed  Google Scholar 

  • Ulvestad E, Williams K, Bo L, Trapp B, Antel J, Mork S (1994) HLA class II molecules (HLA-DR, -DP, -DQ) on cells in the human CNS studied in situ and in vitro. Immunology 82:535–541

    CAS  PubMed  Google Scholar 

  • 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-Goutieres syndrome. Glia 56:568–578

    Article  PubMed  Google Scholar 

  • Ventura R, Harris KM (1999) Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci 19:6897–6906

    CAS  PubMed  Google Scholar 

  • Walz W (2000) Role of astrocytes in the clearance of excess extracellular potassium. Neurochem Int 36:291–300

    Article  CAS  PubMed  Google Scholar 

  • Weber F, Meinl E, Aloisi F, Nevinny-Stickel C, Albert E, Wekerle H, Hohlfeld R (1994) Human astrocytes are only partially competent antigen presenting cells. Possible implications for lesion development in multiple sclerosis. Brain 117(Pt 1):59–69

    Article  PubMed  Google Scholar 

  • Werry EL, Liu GJ, Lovelace MD, Nagarajah R, Hickie IB, Bennett MR (2011) Lipopolysaccharide-stimulated interleukin-10 release from neonatal spinal cord microglia is potentiated by glutamate. Neuroscience 175:93–103

    Article  CAS  PubMed  Google Scholar 

  • Werry EL, Liu GJ, Lovelace MD, Nagarajah R, Bennett MR (2012) Glutamate potentiates lipopolysaccharide-stimulated interleukin-10 release from neonatal rat spinal cord astrocytes. Neuroscience 207:12–24

    Article  CAS  PubMed  Google Scholar 

  • Williams A, Piaton G, Lubetzki C (2007) Astrocytes–friends or foes in multiple sclerosis? Glia 55:1300–1312

    Article  PubMed  Google Scholar 

  • Wong GH, Bartlett PF, Clark-Lewis I, Battye F, Schrader JW (1984) Inducible expression of H-2 and Ia antigens on brain cells. Nature 310:688–691

    Article  CAS  PubMed  Google Scholar 

  • Xie L, Poteet EC, Li W, Scott AE, Liu R, Wen Y, Ghorpade A, Simpkins JW, Yang SH (2010) Modulation of polymorphonuclear neutrophil functions by astrocytes. J Neuroinflammation 7:53

    Article  PubMed  CAS  Google Scholar 

  • Yong VW, Yong FP, Ruijs TC, Antel JP, Kim SU (1991) Expression and modulation of HLA-DR on cultured human adult astrocytes. J Neuropathol Exp Neurol 50:16–28

    Article  CAS  PubMed  Google Scholar 

  • Zeinstra E, Wilczak N, De Keyser J (2000) [3H]dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain. Neurosci Lett 289:75–77

    Article  CAS  PubMed  Google Scholar 

  • Zeinstra E, Wilczak N, De Keyser J (2003) Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7-1 and B7-2. J Neuroimmunol 135:166–171

    Article  CAS  PubMed  Google Scholar 

  • Zeinstra EM, Wilczak N, Wilschut JC, Glazenburg L, Chesik D, Kroese FG, De Keyser J (2006) 5HT4 agonists inhibit interferon-gamma-induced MHC class II and B7 costimulatory molecules expression on cultured astrocytes. J Neuroimmunol 179:191–195

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Dr Scott Preiss and Ms Wendy Stroop for their thoughtful reading of the manuscript and the insightful comments that they provided.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Neurology, Universitair Ziekenhuis Brussel, Center for Neurosciences, Vrije Universiteit Brussel (VUB), Brussels, Belgium

    Cathy J. Jensen & Jacques De Keyser

  2. Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel (VUB), Brussels, Belgium

    Ann Massie

  3. Department of Neurology, Universitair Medisch Centrum Groningen, Rijksuniversiteit Groningen, Groningen, The Netherlands

    Jacques De Keyser

Authors
  1. Cathy J. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ann Massie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jacques De Keyser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cathy J. Jensen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jensen, C.J., Massie, A. & De Keyser, J. Immune Players in the CNS: The Astrocyte. J Neuroimmune Pharmacol 8, 824–839 (2013). https://doi.org/10.1007/s11481-013-9480-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-013-9480-6

Keywords

Search

Navigation