Skip to main content

Advertisement

SpringerLink
Log in

The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Neuroinflammation is the coordinated response of the central nervous system (CNS) to threats to its integrity posed by a variety of conditions, including autoimmunity, pathogens and trauma. Activated astrocytes, in concert with other cellular elements of the CNS and immune system, are important players in the modulation of the neuroinflammatory response. During neurological disease, they produce and respond to cellular signals that often lead to dichotomous processes, which can promote further damage or contribute to repair. This occurs also in multiple sclerosis (MS), where astrocytes are now recognized as key components of its immunopathology. Evidence supporting this role has emerged not only from studies in MS patients, but also from animal models, among which the experimental autoimmune encephalomyelitis (EAE) model has proved especially instrumental. Based on this premise, the purpose of the present review is to summarize the current knowledge of astrocyte behavior in MS and EAE. Following a brief description of the pathological characteristics of the two diseases and the main functional roles of astrocytes in CNS physiology, we will delve into the specific responses of this cell population, analyzing MS and EAE in parallel. We will define the temporal and anatomical profile of astroglial activation, then focus on key processes they participate in. These include: (1) production and response to soluble mediators (e.g., cytokines and chemokines), (2) regulation of oxidative stress, and (3) maintenance of BBB integrity and function. Finally, we will review the state of the art on the available methods to measure astroglial activation in vivo in MS patients, and how this could be exploited to optimize diagnosis, prognosis and treatment decisions. Ultimately, we believe that integrating the knowledge obtained from studies in MS and EAE may help not only better understand the pathophysiology of MS, but also uncover new signals to be targeted for therapeutic intervention.

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
Fig. 4

Similar content being viewed by others

Abbreviations

AhR:

Aryl hydrocarbon receptor

APC:

Antigen presenting cell

AQP4:

Aquaporin-4

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

CFA:

Complete Freund’s adjuvant

CIS:

Clinically isolated syndrome

CLD5:

Claudin-5

CNS:

Central nervous system

CSF:

Cerebro-spinal fluid

Cx43:

Connexin 43

EAE:

Experimental autoimmune encephalomyelitis

ERα:

Estrogen receptor α

GFAP:

Glial fibrillary acidic protein

GM:

Gray matter

HB-EGF:

Heparin-binding epidermal growth factor

ICAM-1:

Intercellular adhesion molecule-1

IFN-I:

Type I interferons

Ins:

Myo-Inositol

LacCer:

Lactosylceramide

MOG:

Myelin oligodendrocyte glycoporotein

MBP:

Myelin basic protein

MRI:

Magnetic resonance imaging

MRS:

Magnetic resonance spectroscopy

MS:

Multiple sclerosis

NADPH:

Nicotinamide adenine dinucleotide phosphate

NAGM:

Normal appearing gray matter

NAWM:

Normal appearing white matter

NGF:

Nerve growth factor

NO:

Nitric oxide

NOS2:

Nitric oxide synthase 2

OCLN:

Occludin

OPC:

Oligodendrocyte precursor cell

PET:

Positron emission tomography

PLP:

Proteolipid protein

PPMS:

Primary progressive multiple sclerosis

ROS:

Reactive oxygen species

RRMS:

Relapsing–remitting multiple sclerosis

S1P:

Sphingosine 1-phosphate

SPMS:

Secondary progressive multiple sclerosis

tCr:

Creatine

TGFβ:

Transforming growth factor β

tNAA:

N-acetylaspartate

TNF:

Tumor necrosis factor

memTNF:

Membrane-bound tumor necrosis factor

solTNF:

Soluble tumor necrosis factor

WM:

White matter

VEGF-A:

Vascular endothelial growth factor A

References

  1. Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53. https://doi.org/10.1038/nrn1824

    Article  CAS  PubMed  Google Scholar 

  2. Abdelhak A, Huss A, Kassubek J, Tumani H, Otto M (2018) Serum GFAP as a biomarker for disease severity in multiple sclerosis. Sci Rep 8:14798. https://doi.org/10.1038/s41598-018-33158-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G et al (2006) Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 203:1007–1019. https://doi.org/10.1084/jem.20051342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alvarez JI, Cayrol R, Prat A (2011) Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta 1812:252–264. https://doi.org/10.1016/j.bbadis.2010.06.017

    Article  CAS  PubMed  Google Scholar 

  5. Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S et al (2011) The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334:1727–1731. https://doi.org/10.1126/science.1206936

    Article  CAS  PubMed  Google Scholar 

  6. Alvarez JI, Katayama T, Prat A (2013) Glial influence on the blood brain barrier. Glia 61:1939–1958. https://doi.org/10.1002/glia.22575

    Article  PubMed  PubMed Central  Google Scholar 

  7. Alvarez JI, Saint-Laurent O, Godschalk A, Terouz S, Briels C, Larouche S et al (2015) Focal disturbances in the blood–brain barrier are associated with formation of neuroinflammatory lesions. Neurobiol Dis 74:14–24. https://doi.org/10.1016/j.nbd.2014.09.016

    Article  CAS  PubMed  Google Scholar 

  8. 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. https://doi.org/10.1002/glia.10193

    Article  PubMed  Google Scholar 

  9. Ambrosini E, Remoli ME, Giacomini E, Rosicarelli B, Serafini B, Lande R et al (2005) Astrocytes produce dendritic cell-attracting chemokines in vitro and in multiple sclerosis lesions. J Neuropathol Exp Neurol 64:706–715

    Article  CAS  PubMed  Google Scholar 

  10. Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R et al (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195–200. https://doi.org/10.1038/nature17623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A (2014) Gliotransmitters travel in time and space. Neuron 81:728–739. https://doi.org/10.1016/j.neuron.2014.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208–215

    Article  CAS  PubMed  Google Scholar 

  13. Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, Mariani JN et al (2012) Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J Clin Invest 122:2454–2468. https://doi.org/10.1172/JCI60842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC et al (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 

  15. Arnold DL, Wolinsky JS, Matthews PM, Falini A (1998) The use of magnetic resonance spectroscopy in the evaluation of the natural history of multiple sclerosis. J Neurol Neurosurg Psychiatry 64(Suppl 1):S94–S101

    PubMed  Google Scholar 

  16. Axelsson M, Malmestrom C, Nilsson S, Haghighi S, Rosengren L, Lycke J (2011) Glial fibrillary acidic protein: a potential biomarker for progression in multiple sclerosis. J Neurol 258:882–888. https://doi.org/10.1007/s00415-010-5863-2

    Article  CAS  PubMed  Google Scholar 

  17. Balashov KE, Rottman JB, Weiner HL, Hancock WW (1999) CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci USA 96:6873–6878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Barateiro A, Afonso V, Santos G, Cerqueira JJ, Brites D, van Horssen J et al (2016) S100B as a potential biomarker and therapeutic target in multiple sclerosis. Mol Neurobiol 53:3976–3991. https://doi.org/10.1007/s12035-015-9336-6

    Article  CAS  PubMed  Google Scholar 

  19. Berman JW, Guida MP, Warren J, Amat J, Brosnan CF (1996) Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat. J Immunol 156:3017–3023

    CAS  PubMed  Google Scholar 

  20. Bjelobaba I, Begovic-Kupresanin V, Pekovic S, Lavrnja I (2018) Animal models of multiple sclerosis: focus on experimental autoimmune encephalomyelitis. J Neurosci Res 96:1021–1042. https://doi.org/10.1002/jnr.24224

    Article  CAS  PubMed  Google Scholar 

  21. Blank T, Prinz M (2017) Type I interferon pathway in CNS homeostasis and neurological disorders. Glia 65:1397–1406. https://doi.org/10.1002/glia.23154

    Article  PubMed  Google Scholar 

  22. Blazevski J, Petkovic F, Momcilovic M, Jevtic B, Mostarica Stojkovic M, Miljkovic D (2015) Tumor necrosis factor stimulates expression of CXCL12 in astrocytes. Immunobiology 220:845–850. https://doi.org/10.1016/j.imbio.2015.01.007

    Article  CAS  PubMed  Google Scholar 

  23. Bo L, Dawson TM, Wesselingh S, Mork S, Choi S, Kong PA (1994) Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol 36:778–786. https://doi.org/10.1002/ana.410360515

    Article  CAS  PubMed  Google Scholar 

  24. Boven LA, Montagne L, Nottet HS, De Groot CJ (2000) Macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and RANTES mRNA semiquantification and protein expression in active demyelinating multiple sclerosis (MS) lesions. Clin Exp Immunol 122:257–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brambilla R, Ashbaugh JJ, Magliozzi R, Dellarole A, Karmally S, Szymkowski DE et al (2011) Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain 134:2736–2754. https://doi.org/10.1093/brain/awr199

    Article  PubMed  PubMed Central  Google Scholar 

  26. Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S et al (2005) Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202:145–156. https://doi.org/10.1084/jem.20041918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brambilla R, Dvoriantchikova G, Barakat D, Ivanov D, Bethea JR, Shestopalov VI (2012) Transgenic inhibition of astroglial NF-kappaB protects from optic nerve damage and retinal ganglion cell loss in experimental optic neuritis. J Neuroinflammation 9:213. https://doi.org/10.1186/1742-2094-9-213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Brambilla R, Morton PD, Ashbaugh JJ, Karmally S, Lambertsen KL, Bethea JR (2014) Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia 62:452–467. https://doi.org/10.1002/glia.22616

    Article  PubMed  Google Scholar 

  29. Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI, Dvoriantchikova G et al (2009) Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J Immunol 182:2628–2640. https://doi.org/10.4049/jimmunol.0802954

    Article  CAS  PubMed  Google Scholar 

  30. Brand A, Richter-Landsberg C, Leibfritz D (1993) Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 15:289–298. https://doi.org/10.1159/000111347

    Article  CAS  PubMed  Google Scholar 

  31. Broholm H, Andersen B, Wanscher B, Frederiksen JL, Rubin I, Pakkenberg B et al (2004) Nitric oxide synthase expression and enzymatic activity in multiple sclerosis. Acta Neurol Scand 109:261–269

    Article  CAS  PubMed  Google Scholar 

  32. Brosnan CF, Raine CS (2013) The astrocyte in multiple sclerosis revisited. Glia 61:453–465. https://doi.org/10.1002/glia.22443

    Article  PubMed  Google Scholar 

  33. Bushong EA, Martone ME, Jones YZ, Ellisman MH (2002) Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 22:183–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Calderon TM, Eugenin EA, Lopez L, Kumar SS, Hesselgesser J, Raine CS et al (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. https://doi.org/10.1016/j.jneuroim.2006.05.003

    Article  CAS  PubMed  Google Scholar 

  35. Camargo N, Brouwers JF, Loos M, Gutmann DH, Smit AB, Verheijen MH (2012) High-fat diet ameliorates neurological deficits caused by defective astrocyte lipid metabolism. FASEB J 26:4302–4315. https://doi.org/10.1096/fj.12-205807

    Article  CAS  PubMed  Google Scholar 

  36. Camargo N, Goudriaan A, van Deijk AF, Otte WM, Brouwers JF, Lodder H et al (2017) Oligodendroglial myelination requires astrocyte-derived lipids. PLoS Biol 15:e1002605. https://doi.org/10.1371/journal.pbio.1002605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Carter SL, Muller 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. https://doi.org/10.1002/glia.20587

    Article  PubMed  Google Scholar 

  38. Chapouly C, Tadesse Argaw A, Horng S, Castro K, Zhang J, Asp L et al (2015) Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions. Brain 138:1548–1567. https://doi.org/10.1093/brain/awv077

    Article  PubMed  PubMed Central  Google Scholar 

  39. Chard DT, Griffin CM, McLean MA, Kapeller P, Kapoor R, Thompson AJ et al (2002) Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis. Brain 125:2342–2352

    Article  CAS  PubMed  Google Scholar 

  40. Chastain EM, Duncan DS, Rodgers JM, Miller SD (2011) The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 1812:265–274. https://doi.org/10.1016/j.bbadis.2010.07.008

    Article  CAS  PubMed  Google Scholar 

  41. Chen H, Sun Y, Lai L, Wu H, Xiao Y, Ming B et al (2015) Interleukin-33 is released in spinal cord and suppresses experimental autoimmune encephalomyelitis in mice. Neuroscience 308:157–168. https://doi.org/10.1016/j.neuroscience.2015.09.019

    Article  CAS  PubMed  Google Scholar 

  42. Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW, Noguchi K et al (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci USA 108:751–756. https://doi.org/10.1073/pnas.1014154108

    Article  PubMed  Google Scholar 

  43. Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A et al (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433. https://doi.org/10.1016/j.cell.2004.12.020

    Article  CAS  PubMed  Google Scholar 

  44. Christophi GP, Gruber RC, Panos M, Christophi RL, Jubelt B, Massa PT (2012) Interleukin-33 upregulation in peripheral leukocytes and CNS of multiple sclerosis patients. Clin Immunol 142:308–319. https://doi.org/10.1016/j.clim.2011.11.007

    Article  CAS  PubMed  Google Scholar 

  45. Colombo E, Cordiglieri C, Melli G, Newcombe J, Krumbholz M, Parada LF et al (2012) Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration. J Exp Med 209:521–535. https://doi.org/10.1084/jem.20110698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Colombo E, Farina C (2016) Astrocytes: key regulators of neuroinflammation. Trends Immunol 37:608–620. https://doi.org/10.1016/j.it.2016.06.006

    Article  CAS  PubMed  Google Scholar 

  47. Constantinescu CS, Farooqi N, O’Brien K, Gran B (2011) Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 164:1079–1106. https://doi.org/10.1111/j.1476-5381.2011.01302.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Corcione A, Casazza S, Ferretti E, Giunti D, Zappia E, Pistorio A (2004) Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc Natl Acad Sci USA 101:11064–11069. https://doi.org/10.1073/pnas.0402455101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. D’Amelio FE, Smith ME, Eng LF (1990) Sequence of tissue responses in the early stages of experimental allergic encephalomyelitis (EAE): immunohistochemical, light microscopic, and ultrastructural observations in the spinal cord. Glia 3:229–240. https://doi.org/10.1002/glia.440030402

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. De Groot CJ, Montagne L, Barten AD, Sminia P, Van Der Valk P (1999) Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 isoforms and TGF-beta type I and type II receptors in multiple sclerosis lesions and human adult astrocyte cultures. J Neuropathol Exp Neurol 58:174–187

    Article  PubMed  Google Scholar 

  52. Ding X, Yan Y, Li X, Li K, Ciric B, Yang J et al (2015) Silencing IFN-gamma binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity. J Immunol 194:4251–4264. https://doi.org/10.4049/jimmunol.1303321

    Article  CAS  PubMed  Google Scholar 

  53. 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. https://doi.org/10.1002/glia.22637

    Article  PubMed  Google Scholar 

  54. Erta M, Giralt M, Jimenez S, Molinero A, Comes G, Hidalgo J (2016) Astrocytic IL-6 influences the clinical symptoms of EAE in mice. Brain Sci 6:15. https://doi.org/10.3390/brainsci6020015

    Article  CAS  PubMed Central  Google Scholar 

  55. Ezan P, Andre P, Cisternino S, Saubamea B, Boulay AC, Doutremer S et al (2012) Deletion of astroglial connexins weakens the blood-brain barrier. J Cereb Blood Flow Metab 32:1457–1467. https://doi.org/10.1038/jcbfm.2012.45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J et al (2012) NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 135:886–899. https://doi.org/10.1093/brain/aws012

    Article  PubMed  PubMed Central  Google Scholar 

  57. Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis–the plaque and its pathogenesis. N Engl J Med 354:942–955. https://doi.org/10.1056/NEJMra052130

    Article  CAS  PubMed  Google Scholar 

  58. Gao H, Danzi MC, Choi CS, Taherian M, Dalby-Hansen C, Ellman DG et al (2017) Opposing functions of microglial and macrophagic TNFR2 in the pathogenesis of experimental autoimmune encephalomyelitis. Cell Rep 18:198–212. https://doi.org/10.1016/j.celrep.2016.11.083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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 USA 107:8416–8421. https://doi.org/10.1073/pnas.0910627107

    Article  PubMed  PubMed Central  Google Scholar 

  60. Glabinski AR, Tani M, Strieter RM, Tuohy VK, Ransohoff RM (1997) Synchronous synthesis of alpha- and beta-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. Am J Pathol 150:617–630

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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. https://doi.org/10.1006/brbi.1995.1030

    Article  CAS  PubMed  Google Scholar 

  62. Goverman J, Woods A, Larson L, Weiner LP, Hood L, Zaller DM (1993) Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72:551–560

    Article  CAS  PubMed  Google Scholar 

  63. Greenfield AL, Hauser SL (2018) B-cell therapy for multiple sclerosis: entering an era. Ann Neurol 83:13–26. https://doi.org/10.1002/ana.25119

    Article  PubMed  PubMed Central  Google Scholar 

  64. Grist JJ, Marro BS, Skinner DD, Syage AR, Worne C, Doty DJ et al (2018) Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment. Eur J Immunol 48:1199–1210. https://doi.org/10.1002/eji.201747442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Guerrini MM, Okamoto K, Komatsu N, Sawa S, Danks L, Penninger JM et al (2015) Inhibition of the TNF family cytokine RANKL prevents autoimmune inflammation in the central nervous system. Immunity 43:1174–1185. https://doi.org/10.1016/j.immuni.2015.10.017

    Article  CAS  PubMed  Google Scholar 

  66. Guo F, Maeda Y, Ma J, Delgado M, Sohn J, Miers L et al (2011) Macroglial plasticity and the origins of reactive astroglia in experimental autoimmune encephalomyelitis. J Neurosci 31:11914–11928. https://doi.org/10.1523/JNEUROSCI.1759-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Habbas S, Santello M, Becker D, Stubbe H, Zappia G, Liaudet N et al (2015) Neuroinflammatory TNFalpha impairs memory via astrocyte signaling. Cell 163:1730–1741. https://doi.org/10.1016/j.cell.2015.11.023

    Article  CAS  PubMed  Google Scholar 

  68. Harbige LS, Layward L, Morris-Downes MM, Dumonde DC, Amor S (2000) The protective effects of omega-6 fatty acids in experimental autoimmune encephalomyelitis (EAE) in relation to transforming growth factor-beta 1 (TGF-beta1) up-regulation and increased prostaglandin E2 (PGE2) production. Clin Exp Immunol 122:445–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hayden MS, Ghosh S (2014) Regulation of NF-kappaB by TNF family cytokines. Semin Immunol 26:253–266. https://doi.org/10.1016/j.smim.2014.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Higashi K, Fujita A, Inanobe A, Tanemoto M, Doi K, Kubo T et al (2001) An inwardly rectifying K(+) channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am J Physiol Cell Physiol 281:C922–931. https://doi.org/10.1152/ajpcell.2001.281.3.c922

    Article  CAS  PubMed  Google Scholar 

  71. Hindinger C, Bergmann CC, Hinton DR, Phares TW, Parra GI, Hussain S et al (2012) IFN-gamma signaling to astrocytes protects from autoimmune mediated neurological disability. PLoS One 7:e42088. https://doi.org/10.1371/journal.pone.0042088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hofman FM, Hinton DR, Johnson K, Merrill JE (1989) Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 170:607–612

    Article  CAS  PubMed  Google Scholar 

  73. Hogel H, Rissanen E, Barro C, Matilainen M, Nylund M, Kuhle J et al (2018) Serum glial fibrillary acidic protein correlates with multiple sclerosis disease severity. Mult Scler. https://doi.org/10.1177/1352458518819380

    Article  PubMed  Google Scholar 

  74. Holley JE, Newcombe J, Winyard PG, Gutowski NJ (2007) Peroxiredoxin V in multiple sclerosis lesions: predominant expression by astrocytes. Mult Scler 13:955–961. https://doi.org/10.1177/1352458507078064

    Article  CAS  PubMed  Google Scholar 

  75. Horng S, Therattil A, Moyon S, Gordon A, Kim K, Argaw AT et al (2017) Astrocytic tight junctions control inflammatory CNS lesion pathogenesis. J Clin Invest 127:3136–3151. https://doi.org/10.1172/JCI91301

    Article  PubMed  PubMed Central  Google Scholar 

  76. Hulshof S, Montagne L, De Groot CJ, 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

    Article  PubMed  Google Scholar 

  77. Ishikawa M, Jin Y, Guo H, Link H, Xiao BG (1999) Nasal administration of transforming growth factor-beta1 induces dendritic cells and inhibits protracted-relapsing experimental allergic encephalomyelitis. Mult Scler 5:184–191. https://doi.org/10.1177/135245859900500308

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Karim H, Kim SH, Lapato AS, Yasui N, Katzenellenbogen JA, Tiwari-Woodruff SK (2018) Increase in chemokine CXCL1 by ERbeta ligand treatment is a key mediator in promoting axon myelination. Proc Natl Acad Sci USA 115:6291–6296. https://doi.org/10.1073/pnas.1721732115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kassubek R, Gorges M, Schocke M, Hagenston VAM, Huss A, Ludolph AC et al (2017) GFAP in early multiple sclerosis: a biomarker for inflammation. Neurosci Lett 657:166–170. https://doi.org/10.1016/j.neulet.2017.07.050

    Article  CAS  PubMed  Google Scholar 

  81. Keaney J, Campbell M (2015) The dynamic blood-brain barrier. FEBS J 282:4067–4079. https://doi.org/10.1111/febs.13412

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kirov II, Liu S, Tal A, Wu WE, Davitz MS, Babb JS et al (2017) Proton MR spectroscopy of lesion evolution in multiple sclerosis: steady-state metabolism and its relationship to conventional imaging. Hum Brain Mapp 38:4047–4063. https://doi.org/10.1002/hbm.23647

    Article  PubMed  PubMed Central  Google Scholar 

  84. Kivisakk P, Imitola J, Rasmussen S, Elyaman W, Zhu B, Ransohoff RM et al (2009) Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol 65:457–469. https://doi.org/10.1002/ana.21379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Koehler RC, Roman RJ, Harder DR (2009) Astrocytes and the regulation of cerebral blood flow. Trends Neurosci 32:160–169. https://doi.org/10.1016/j.tins.2008.11.005

    Article  CAS  PubMed  Google Scholar 

  86. Kothavale A, DiGregorio D, Smith ME (1995) Glial fibrillary acidic protein mRNA and the development of gliosis in mice with chronic relapsing experimental allergic encephalomyelitis. Prog Brain Res 105:305–310

    Article  CAS  PubMed  Google Scholar 

  87. Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisakk P, Ransohoff RM et al (2006) Chemokines in multiple sclerosis: cXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 129:200–211. https://doi.org/10.1093/brain/awh680

    Article  PubMed  Google Scholar 

  88. Krumbholz M, Theil D, Derfuss T, Rosenwald A, Schrader F, Monoranu CM et al (2005) BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J Exp Med 201:195–200. https://doi.org/10.1084/jem.20041674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712. https://doi.org/10.1093/brain/awh641

    Article  PubMed  Google Scholar 

  90. Lanz TV, Ding Z, Ho PP, Luo J, Agrawal AN, Srinagesh H et al (2010) Angiotensin II sustains brain inflammation in mice via TGF-beta. J Clin Invest 120:2782–2794. https://doi.org/10.1172/JCI41709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lassmann H, van Horssen J, Mahad D (2012) Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 8:647–656. https://doi.org/10.1038/nrneurol.2012.168

    Article  CAS  PubMed  Google Scholar 

  92. Lee DH, Geyer E, Flach AC, Jung K, Gold R, Flugel A et al (2012) Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination. Acta Neuropathol 123:247–258. https://doi.org/10.1007/s00401-011-0890-3

    Article  CAS  PubMed  Google Scholar 

  93. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. https://doi.org/10.1038/nature21029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Liedtke W, Edelmann W, Chiu FC, Kucherlapati R, Raine CS (1998) Experimental autoimmune encephalomyelitis in mice lacking glial fibrillary acidic protein is characterized by a more severe clinical course and an infiltrative central nervous system lesion. Am J Pathol 152:251–259

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Linington C, Lassmann H (1987) Antibody responses in chronic relapsing experimental allergic encephalomyelitis: correlation of serum demyelinating activity with antibody titre to the myelin/oligodendrocyte glycoprotein (MOG). J Neuroimmunol 17:61–69

    Article  CAS  PubMed  Google Scholar 

  96. Linker RA, Lee DH, Demir S, Wiese S, Kruse N, Siglienti I et al (2010) Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis. Brain 133:2248–2263. https://doi.org/10.1093/brain/awq179

    Article  PubMed  Google Scholar 

  97. 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. https://doi.org/10.1016/S0002-9440(10)64677-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Liu X, He F, Pang R, Zhao D, Qiu W et al (2014) Interleukin-17 (IL-17)-induced microRNA 873 (miR-873) contributes to the pathogenesis of experimental autoimmune encephalomyelitis by targeting A20 ubiquitin-editing enzyme. J Biol Chem 289:28971–28986. https://doi.org/10.1074/jbc.M114.577429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Llufriu S, Kornak J, Ratiney H, Oh J, Brenneman D, Cree BA et al (2014) Magnetic resonance spectroscopy markers of disease progression in multiple sclerosis. JAMA Neurol 71:840–847. https://doi.org/10.1001/jamaneurol.2014.895

    Article  PubMed  Google Scholar 

  100. Luchetti S, van Eden CG, Schuurman K, van Strien ME, Swaab DF, Huitinga I (2014) Gender differences in multiple sclerosis: induction of estrogen signaling in male and progesterone signaling in female lesions. J Neuropathol Exp Neurol 73:123–135. https://doi.org/10.1097/NEN.0000000000000037

    Article  CAS  PubMed  Google Scholar 

  101. Ludwin SK, Rao V, Moore CS, Antel JP (2016) Astrocytes in multiple sclerosis. Mult Scler 22:1114–1124. https://doi.org/10.1177/1352458516643396

    Article  CAS  PubMed  Google Scholar 

  102. Luo J, Ho P, Steinman L, Wyss-Coray T (2008) Bioluminescence in vivo imaging of autoimmune encephalomyelitis predicts disease. J Neuroinflammation 5:6. https://doi.org/10.1186/1742-2094-5-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Luo J, Ho PP, Buckwalter MS, Hsu T, Lee LY, Zhang H et al (2007) Glia-dependent TGF-beta signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis. J Clin Invest 117:3306–3315. https://doi.org/10.1172/JCI31763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Magliozzi R, Howell OW, Nicholas R, Cruciani C, Castellaro M, Romualdi C et al (2018) Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Ann Neurol 83:739–755. https://doi.org/10.1002/ana.25197

    Article  CAS  PubMed  Google Scholar 

  105. Mahad DH, Trapp BD, Lassmann H (2015) Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 14:183–193. https://doi.org/10.1016/S1474-4422(14)70256-X

    Article  CAS  PubMed  Google Scholar 

  106. Maimone D, Guazzi GC, Annunziata P (1997) IL-6 detection in multiple sclerosis brain. J Neurol Sci 146:59–65

    Article  CAS  PubMed  Google Scholar 

  107. Malmestrom C, Haghighi S, Rosengren L, Andersen O, Lycke J (2003) Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology 61:1720–1725

    Article  CAS  PubMed  Google Scholar 

  108. Markoullis K, Sargiannidou I, Schiza N, Hadjisavvas A, Roncaroli F, Reynolds R et al (2012) Gap junction pathology in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol 123:873–886. https://doi.org/10.1007/s00401-012-0978-4

    Article  CAS  PubMed  Google Scholar 

  109. Markoullis K, Sargiannidou I, Schiza N, Roncaroli F, Reynolds R, Kleopa KA (2014) Oligodendrocyte gap junction loss and disconnection from reactive astrocytes in multiple sclerosis gray matter. J Neuropathol Exp Neurol 73:865–879. https://doi.org/10.1097/NEN.0000000000000106

    Article  CAS  PubMed  Google Scholar 

  110. Martinez MA, Olsson B, Bau L, Matas E, Cobo Calvo A, Andreasson U et al (2015) Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis. Mult Scler 21:550–561. https://doi.org/10.1177/1352458514549397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Masaki K (2015) Early disruption of glial communication via connexin gap junction in multiple sclerosis, Balo’s disease and neuromyelitis optica. Neuropathology 35:469–480. https://doi.org/10.1111/neup.12211

    Article  CAS  PubMed  Google Scholar 

  112. Masaki K, Suzuki SO, Matsushita T, Matsuoka T, Imamura S, Yamasaki R et al (2013) Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica. PLoS One 8:e72919. https://doi.org/10.1371/journal.pone.0072919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Mayo L, Trauger SA, Blain M, Nadeau M, Patel B, Alvarez JI et al (2014) Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 20:1147–1156. https://doi.org/10.1038/nm.3681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. McCandless EE, Piccio L, Woerner BM, Schmidt RE, Rubin JB, Cross AH et al (2008) Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis. Am J Pathol 172:799–808. https://doi.org/10.2353/ajpath.2008.070918

    Article  PubMed  PubMed Central  Google Scholar 

  115. 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 

  116. McManus C, Berman JW, Brett FM, Staunton H, Farrell M, Brosnan CF (1998) MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study. J Neuroimmunol 86:20–29

    Article  CAS  PubMed  Google Scholar 

  117. 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. https://doi.org/10.1002/glia.22307

    Article  PubMed  Google Scholar 

  118. 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. https://doi.org/10.1084/jem.20080730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Memet S (2006) NF-kappaB functions in the nervous system: from development to disease. Biochem Pharmacol 72:1180–1195. https://doi.org/10.1016/j.bcp.2006.09.003

    Article  CAS  PubMed  Google Scholar 

  120. Micera A, Vigneti E, Aloe L (1998) Changes of NGF presence in nonneuronal cells in response to experimental allergic encephalomyelitis in Lewis rats. Exp Neurol 154:41–46. https://doi.org/10.1006/exnr.1998.6864

    Article  CAS  PubMed  Google Scholar 

  121. Mills Ko E, Ma JH, Guo F, Miers L, Lee E, Bannerman P 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. https://doi.org/10.1186/1742-2094-11-105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Miyagishi R, Kikuchi S, Takayama C, Inoue Y, Tashiro K (1997) Identification of cell types producing RANTES, MIP-1 alpha and MIP-1 beta in rat experimental autoimmune encephalomyelitis by in situ hybridization. J Neuroimmunol 77:17–26

    Article  CAS  PubMed  Google Scholar 

  123. Moreno M, Bannerman P, Ma J, Guo F, Miers L, Soulika AM et al (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. https://doi.org/10.1523/JNEUROSCI.1137-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mossakowski AA, Pohlan J, Bremer D, Lindquist R, Millward JM, Bock M et al (2015) Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation. Acta Neuropathol 130:799–814. https://doi.org/10.1007/s00401-015-1497-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Nguyen D, Stangel M (2001) Expression of the chemokine receptors CXCR1 and CXCR2 in rat oligodendroglial cells. Brain Res Dev Brain Res 128:77–81

    Article  CAS  PubMed  Google Scholar 

  126. Nijland PG, Michailidou I, Witte ME, Mizee MR, van der Pol SM, van Het Hof B et al (2014) Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions. Glia 62:1125–1141. https://doi.org/10.1002/glia.22667

    Article  PubMed  Google Scholar 

  127. Nijland PG, Witte ME, van het Hof B, van der Pol S, Bauer J, Lassmann H et al (2014) Astroglial PGC-1alpha increases mitochondrial antioxidant capacity and suppresses inflammation: implications for multiple sclerosis. Acta Neuropathol Commun 2:170. https://doi.org/10.1186/s40478-014-0170-2

    Article  PubMed  PubMed Central  Google Scholar 

  128. Noell S, Wolburg-Buchholz K, Mack AF, Beedle AM, Satz JS, Campbell KP et al (2011) Evidence for a role of dystroglycan regulating the membrane architecture of astroglial endfeet. Eur J Neurosci 33:2179–2186. https://doi.org/10.1111/j.1460-9568.2011.07688.x

    Article  PubMed  PubMed Central  Google Scholar 

  129. Nylander A, Hafler DA (2012) Multiple sclerosis. J Clin Invest 122:1180–1188. https://doi.org/10.1172/JCI58649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Obert D, Helms G, Sattler MB, Jung K, Kretzschmar B, Bahr M et al (2016) Brain metabolite changes in patients with relapsing-remitting and secondary progressive multiple sclerosis: a two-year follow-up study. PLoS One 11:e0162583. https://doi.org/10.1371/journal.pone.0162583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Okada M, Nakao R, Momosaki S, Yanamoto K, Kikuchi T, Okamura T et al (2013) Improvement of brain uptake for in vivo PET imaging of astrocytic oxidative metabolism using benzyl [1-(11)C]acetate. Appl Radiat Isot 78:102–107. https://doi.org/10.1016/j.apradiso.2013.04.025

    Article  CAS  PubMed  Google Scholar 

  132. Oliet SH, Piet R, Poulain DA (2001) Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science 292:923–926. https://doi.org/10.1126/science.1059162

    Article  CAS  PubMed  Google Scholar 

  133. Omari KM, John G, Lango R, Raine CS (2006) Role for CXCR2 and CXCL1 on glia in multiple sclerosis. Glia 53:24–31. https://doi.org/10.1002/glia.20246

    Article  PubMed  Google Scholar 

  134. Omari KM, Lutz SE, Santambrogio L, Lira SA, Raine CS (2009) Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1. Am J Pathol 174:164–176. https://doi.org/10.2353/ajpath.2009.080350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Panitch HS, McFarlin DE (1977) Experimental allergic encephalomyelitis: enhancement of cell-mediated transfer by concanavalin A. J Immunol 119:1134–1137

    CAS  PubMed  Google Scholar 

  136. Patel JR, McCandless EE, Dorsey D, Klein RS (2010) CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination. Proc Natl Acad Sci USA 107:11062–11067. https://doi.org/10.1073/pnas.1006301107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Patel JR, Williams JL, Muccigrosso MM, Liu L, Sun T, Rubin JB et al (2012) Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS. Acta Neuropathol 124:847–860. https://doi.org/10.1007/s00401-012-1034-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Pekny M, Pekna M, Messing A, Steinhauser C, Lee JM, Parpura V et al (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345. https://doi.org/10.1007/s00401-015-1513-1

    Article  CAS  PubMed  Google Scholar 

  140. Petzold A, Eikelenboom MJ, Gveric D, Keir G, Chapman M, Lazeron RH et al (2002) Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations. Brain 125:1462–1473

    Article  CAS  PubMed  Google Scholar 

  141. Pham H, Ramp AA, Klonis N, Ng SW, Klopstein A, Ayers MM et al (2009) The astrocytic response in early experimental autoimmune encephalomyelitis occurs across both the grey and white matter compartments. J Neuroimmunol 208:30–39. https://doi.org/10.1016/j.jneuroim.2008.12.010

    Article  CAS  PubMed  Google Scholar 

  142. Phelps CH (1972) Barbiturate-induced glycogen accumulation in brain. An electron microscopic study. Brain Res 39:225–234

    Article  CAS  PubMed  Google Scholar 

  143. Plumb J, McQuaid S, Cross AK, Surr J, Haddock G, Bunning RA et al (2006) Upregulation of ADAM-17 expression in active lesions in multiple sclerosis. Mult Scler 12:375–385. https://doi.org/10.1191/135248506ms1276oa

    Article  CAS  PubMed  Google Scholar 

  144. Ponath G, Ramanan S, Mubarak M, Housley W, Lee S, Sahinkaya FR et al (2017) Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology. Brain 140:399–413. https://doi.org/10.1093/brain/aww298

    Article  PubMed  Google Scholar 

  145. Ponde DE, Dence CS, Oyama N, Kim J, Tai YC, Laforest R (2007) 18F-fluoroacetate: a potential acetate analog for prostate tumor imaging–in vivo evaluation of 18F-fluoroacetate versus 11C-acetate. J Nucl Med 48:420–428

    CAS  PubMed  Google Scholar 

  146. Poutiainen P, Jaronen M, Quintana FJ, Brownell AL (2016) Precision medicine in multiple sclerosis: future of PET imaging of inflammation and reactive astrocytes. Front Mol Neurosci 9:85. https://doi.org/10.3389/fnmol.2016.00085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Prins M, Dutta R, Baselmans B, Breve JJ, Bol JG, Deckard SA et al (2014) Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis patients. Acta Neuropathol Commun 2:98. https://doi.org/10.1186/s40478-014-0098-6

    Article  PubMed  PubMed Central  Google Scholar 

  148. Probert L (2015) TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience 302:2–22. https://doi.org/10.1016/j.neuroscience.2015.06.038

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  150. Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O (2011) The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol 122:155–170. https://doi.org/10.1007/s00401-011-0840-0

    Article  PubMed  Google Scholar 

  151. Rosengren LE, Lycke J, Andersen O (1995) Glial fibrillary acidic protein in CSF of multiple sclerosis patients: relation to neurological deficit. J Neurol Sci 133:61–65

    Article  CAS  PubMed  Google Scholar 

  152. Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC et al (2018) Microglial control of astrocytes in response to microbial metabolites. Nature 557:724–728. https://doi.org/10.1038/s41586-018-0119-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA, Borucki DM et al (2017) Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci USA 114:2012–2017. https://doi.org/10.1073/pnas.1615413114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L et al (2016) 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. https://doi.org/10.1038/nm.4106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 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. https://doi.org/10.4049/jimmunol.1002188

    Article  CAS  PubMed  Google Scholar 

  156. Savarin C, Hinton DR, Valentin-Torres A, Chen Z, Trapp BD (2015) Astrocyte response to IFN-gamma limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis. J Neuroinflammation 12:79. https://doi.org/10.1186/s12974-015-0293-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813:878–888. https://doi.org/10.1016/j.bbamcr.2011.01.034

    Article  CAS  PubMed  Google Scholar 

  158. Schenk GJ, Dijkstra S, van het Hof AJ, van der Pol SM, Drexhage JA, van der Valk P et al (2013) Roles for HB-EGF and CD9 in multiple sclerosis. Glia 61:1890–1905. https://doi.org/10.1002/glia.22565

    Article  PubMed  Google Scholar 

  159. Schonrock LM, Gawlowski G, Bruck W (2000) Interleukin-6 expression in human multiple sclerosis lesions. Neurosci Lett 294:45–48

    Article  CAS  PubMed  Google Scholar 

  160. Seabrook TJ, Littlewood-Evans A, Brinkmann V, Pollinger B, Schnell C, Hiestand PC (2010) Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions. J Neuroinflammation 7:95. https://doi.org/10.1186/1742-2094-7-95

    Article  PubMed  PubMed Central  Google Scholar 

  161. Selmaj K, Raine CS, Cannella B, Brosnan CF (1991) Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J Clin Invest 87:949–954. https://doi.org/10.1172/JCI115102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Senecal V, Deblois G, Beauseigle D, Schneider R, Brandenburg J, Newcombe J et al (2016) Production of IL-27 in multiple sclerosis lesions by astrocytes and myeloid cells: modulation of local immune responses. Glia 64:553–569. https://doi.org/10.1002/glia.22948

    Article  PubMed  Google Scholar 

  163. Serafini B, Magliozzi R, Rosicarelli B, Reynolds R, Zheng TS, Aloisi F (2008) Expression of TWEAK and its receptor Fn14 in the multiple sclerosis brain: implications for inflammatory tissue injury. J Neuropathol Exp Neurol 67:1137–1148. https://doi.org/10.1097/NEN.0b013e31818dab90

    Article  PubMed  Google Scholar 

  164. Shan K, Pang R, Zhao C, Liu X, Gao W, Zhang J (2017) IL-17-triggered downregulation of miR-497 results in high HIF-1alpha expression and consequent IL-1beta and IL-6 production by astrocytes in EAE mice. Cell Mol Immunol. https://doi.org/10.1038/cmi.2017.12

    Article  PubMed  PubMed Central  Google Scholar 

  165. Simard M, Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129:877–896. https://doi.org/10.1016/j.neuroscience.2004.09.053

    Article  CAS  PubMed  Google Scholar 

  166. Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN (2000) Expression of the interferon-gamma-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions. Neuropathol Appl Neurobiol 26:133–142

    Article  CAS  PubMed  Google Scholar 

  167. Sinclair C, Kirk J, Herron B, Fitzgerald U, McQuaid S (2007) Absence of aquaporin-4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol 113:187–194. https://doi.org/10.1007/s00401-006-0169-2

    Article  CAS  PubMed  Google Scholar 

  168. Smith ME, Somera FP, Eng LF (1983) Immunocytochemical staining for glial fibrillary acidic protein and the metabolism of cytoskeletal proteins in experimental allergic encephalomyelitis. Brain Res 264:241–253

    Article  CAS  PubMed  Google Scholar 

  169. Sofroniew MV (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 16:249–263. https://doi.org/10.1038/nrn3898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647. https://doi.org/10.1016/j.tins.2009.08.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. https://doi.org/10.1007/s00401-009-0619-8

    Article  PubMed  Google Scholar 

  172. Solana E, Martinez-Heras E, Martinez-Lapiscina EH, Sepulveda M, Sola-Valls N, Bargallo N et al (2018) Magnetic resonance markers of tissue damage related to connectivity disruption in multiple sclerosis. Neuroimage Clin 20:161–168. https://doi.org/10.1016/j.nicl.2018.07.012

    Article  PubMed  PubMed Central  Google Scholar 

  173. Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA 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. https://doi.org/10.1172/JCI5150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Sorensen TL, Trebst C, Kivisakk P, Klaege KL, Majmudar A, Ravid R 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  CAS  PubMed  Google Scholar 

  175. Spence RD, Hamby ME, Umeda E, Itoh N, Du S, Wisdom AJ et al (2011) Neuroprotection mediated through estrogen receptor-alpha in astrocytes. Proc Natl Acad Sci USA 108:8867–8872. https://doi.org/10.1073/pnas.1103833108

    Article  PubMed  PubMed Central  Google Scholar 

  176. Spence RD, Wisdom AJ, Cao Y, Hill HM, Mongerson CR, Stapornkul B et al (2013) Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERalpha signaling on astrocytes but not through ERbeta signaling on astrocytes or neurons. J Neurosci 33:10924–10933. https://doi.org/10.1523/JNEUROSCI.0886-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H (2002) BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125:75–85

    Article  PubMed  Google Scholar 

  178. Takata K, Kato H, Shimosegawa E, Okuno T, Koda T, Sugimoto T et al (2014) 11C-acetate PET imaging in patients with multiple sclerosis. PLoS One 9:e111598. https://doi.org/10.1371/journal.pone.0111598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Taniguchi K, Karin M (2018) NF-kappaB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 18:309–324. https://doi.org/10.1038/nri.2017.142

    Article  CAS  PubMed  Google Scholar 

  180. Toft-Hansen H, Fuchtbauer L, Owens T (2011) Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease. Glia 59:166–176. https://doi.org/10.1002/glia.21088

    Article  PubMed  Google Scholar 

  181. Trajkovic V, Stosic-Grujicic S, Samardzic T, Markovic M, Miljkovic D, Ramic Z et al (2001) Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes. J Neuroimmunol 119:183–191

    Article  CAS  PubMed  Google Scholar 

  182. Tran EH, Hardin-Pouzet H, Verge G, Owens T (1997) Astrocytes and microglia express inducible nitric oxide synthase in mice with experimental allergic encephalomyelitis. J Neuroimmunol 74:121–129

    Article  CAS  PubMed  Google Scholar 

  183. Van Der Voorn P, Tekstra J, Beelen RH, Tensen CP, Van Der Valk P, De Groot CJ (1999) Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions. Am J Pathol 154:45–51. https://doi.org/10.1016/S0002-9440(10)65249-2

    Article  Google Scholar 

  184. Van Doorn R, Van Horssen J, Verzijl D, Witte M, Ronken E, Van Het Hof B et al (2010) Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia 58:1465–1476. https://doi.org/10.1002/glia.21021

    Article  PubMed  Google Scholar 

  185. van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra CD, van der Valk P et al (2008) Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med 45:1729–1737. https://doi.org/10.1016/j.freeradbiomed.2008.09.023

    Article  CAS  PubMed  Google Scholar 

  186. van Loo G, De Lorenzi R, Schmidt H, Huth M, Mildner A, Schmidt-Supprian M et al (2006) Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat Immunol 7:954–961. https://doi.org/10.1038/ni1372

    Article  CAS  PubMed  Google Scholar 

  187. Verkhratsky A, Nedergaard M (2018) Physiology of astroglia. Physiol Rev 98:239–389. https://doi.org/10.1152/physrev.00042.2016

    Article  CAS  PubMed  Google Scholar 

  188. Villarroya H, Violleau K, Ben Younes-Chennoufi A, Baumann N (1996) Myelin-induced experimental allergic encephalomyelitis in Lewis rats: tumor necrosis factor alpha levels in serum and cerebrospinal fluid immunohistochemical expression in glial cells and macrophages of optic nerve and spinal cord. J Neuroimmunol 64:55–61

    Article  CAS  PubMed  Google Scholar 

  189. Voigt D, Scheidt U, Derfuss T, Bruck W, Junker A (2017) Expression of the antioxidative enzyme peroxiredoxin 2 in multiple sclerosis lesions in relation to inflammation. Int J Mol Sci 18:760. https://doi.org/10.3390/ijms18040760

    Article  CAS  PubMed Central  Google Scholar 

  190. Vos CM, Geurts JJ, Montagne L, van Haastert ES, Bo L, van der Valk P et al (2005) Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis. Neurobiol Dis 20:953–960. https://doi.org/10.1016/j.nbd.2005.06.012

    Article  CAS  PubMed  Google Scholar 

  191. Voskuhl RR, Peterson RS, Song B, Ao Y, Morales LB, Tiwari-Woodruff S et al (2009) Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J Neurosci 29:11511–11522. https://doi.org/10.1523/JNEUROSCI.1514-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Wallin MT (2017) The prevalence of multiple sclerosis in the united states: a population-based healthcare database approach. In: ECTRIMS Online Library. https://onlinelibrary.ectrims-congress.eu/ectrims/2017/ACTRIMS-ECTRIMS2017/199999/. Accessed 21 Jan 2019

  193. Wang D, Ayers MM, Catmull DV, Hazelwood LJ, Bernard CC, Orian JM (2005) Astrocyte-associated axonal damage in pre-onset stages of experimental autoimmune encephalomyelitis. Glia 51:235–240. https://doi.org/10.1002/glia.20199

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  195. Wang X, Haroon F, Karray S, Martina D, Schluter D (2013) Astrocytic Fas ligand expression is required to induce T-cell apoptosis and recovery from experimental autoimmune encephalomyelitis. Eur J Immunol 43:115–124. https://doi.org/10.1002/eji.201242679

    Article  CAS  PubMed  Google Scholar 

  196. Wang Y, Imitola J, Rasmussen S, O’Connor KC, Khoury SJ (2008) Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann Neurol 64:417–427. https://doi.org/10.1002/ana.21457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Wolburg-Buchholz K, Mack AF, Steiner E, Pfeiffer F, Engelhardt B, Wolburg H (2009) Loss of astrocyte polarity marks blood-brain barrier impairment during experimental autoimmune encephalomyelitis. Acta Neuropathol 118:219–233. https://doi.org/10.1007/s00401-009-0558-4

    Article  CAS  PubMed  Google Scholar 

  198. Wyss-Coray T, Borrow P, Brooker MJ, Mucke L (1997) Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice. J Neuroimmunol 77:45–50

    Article  CAS  PubMed  Google Scholar 

  199. Wyss MT, Magistretti PJ, Buck A, Weber B (2011) Labeled acetate as a marker of astrocytic metabolism. J Cereb Blood Flow Metab 31:1668–1674. https://doi.org/10.1038/jcbfm.2011.84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Wyss MT, Weber B, Treyer V, Heer S, Pellerin L, Magistretti PJ et al (2009) Stimulation-induced increases of astrocytic oxidative metabolism in rats and humans investigated with 1-11C-acetate. J Cereb Blood Flow Metab 29:44–56. https://doi.org/10.1038/jcbfm.2008.86

    Article  CAS  PubMed  Google Scholar 

  201. Yun HM, Park KR, Kim EC, Hong JT (2015) PRDX6 controls multiple sclerosis by suppressing inflammation and blood brain barrier disruption. Oncotarget 6:20875–20884. https://doi.org/10.18632/oncotarget.5205

    Article  PubMed  PubMed Central  Google Scholar 

  202. Zarruk JG, Berard JL, Passos dos Santos R, Kroner A, Lee J, Arosio P et al (2015) Expression of iron homeostasis proteins in the spinal cord in experimental autoimmune encephalomyelitis and their implications for iron accumulation. Neurobiol Dis 81:93–107. https://doi.org/10.1016/j.nbd.2015.02.001

    Article  CAS  PubMed  Google Scholar 

  203. Zhou D, Srivastava R, Nessler S, Grummel V, Sommer N, Bruck W et al (2006) Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc Natl Acad Sci USA 103:19057–19062. https://doi.org/10.1073/pnas.0607242103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to Geoffrey Taghon for his contribution to the graphic design of Fig. 4. R.B. was supported by NIH-NINDS (grant 1R01NS094522-01), the Italian Multiple Sclerosis Foundation (grant FISM 2015/R/7), the US National Multiple Sclerosis Society (grant NMSS PP-1804-30716), and The Miami Project To Cure Paralysis.

Author information

Authors and Affiliations

  1. The Miami Project To Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Roberta Brambilla

  2. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Roberta Brambilla

  3. Department of Clinical Research, BRIDGE-Brain Research-Inter-Disciplinary Guided Excellence, University of Southern Denmark, Odense C, Denmark

    Roberta Brambilla

Authors
  1. Roberta Brambilla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberta Brambilla.

Ethics declarations

Conflict of interest

The author declares no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brambilla, R. The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol 137, 757–783 (2019). https://doi.org/10.1007/s00401-019-01980-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-019-01980-7

Keywords

Search

Navigation