Top

Published in:

Open Access 01-12-2015 | Research

Role of glial 14-3-3 gamma protein in autoimmune demyelination

Authors: De-Hyung Lee, Petra Steinacker, Silvia Seubert, Tanja Turnescu, Arthur Melms, Arndt Manzel, Markus Otto, Ralf A. Linker

Published in: Journal of Neuroinflammation | Issue 1/2015

Abstract

Background

The family of 14-3-3 proteins plays an important role in the regulation of cell survival and death. Here, we investigate the role of the 14-3-3 gamma (14-3-3 γ) subunit for glial responses in autoimmune demyelination.

Methods

Expression of 14-3-3 γ in glial cell culture was investigated by reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. 14-3-3 γ knockout mice were subjected to murine myelin oligodendrocyte-induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of multiple sclerosis (MS).

Results

Expression studies in cell culture confined expression of 14-3-3 γ to both, oligodendrocytes (OL) and astrocytes. RT-PCR analysis revealed an increased expression of 14-3-3 γ mRNA in the spinal cord during the late chronic phase of MOG-EAE. At that stage, EAE was more severe in 14-3-3 γ knockout mice as compared to age- and gender-matched controls. Histopathological analyses on day 56 post immunization (p.i.) revealed significantly enhanced myelin damage as well as OL injury and secondary, an increase in axonal injury and gliosis in 14-3-3 γ −/− mice. At the same time, deficiency in 14-3-3 γ protein did not influence the immune response. Further histological studies revealed an increased susceptibility towards apoptosis in 14-3-3 γ-deficient OL in the inflamed spinal cord.

Conclusion

These data argue for a pivotal role of 14-3-3 γ-mediated signalling pathways for OL protection in neuroinflammation.

Available only for authorised users

Butt AQ, Ahmed S, Maratha A, Miggin SM. 14-3-3epsilon and 14-3-3sigma inhibit Toll-like receptor (TLR)-mediated proinflammatory cytokine induction. J Biol Chem. 2012;287(46):38665–79.PubMedCentralCrossRefPubMed

Butzkueven H, Zhang JG, Soilu-Hanninen M, Hochrein H, Chionh F, Shipham KA, et al. LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat Med. 2002;8(6):613–9.CrossRefPubMed

Chen XQ, Fung YW, Yu AC. Association of 14-3-3gamma and phosphorylated bad attenuates injury in ischemic astrocytes. J Cereb Blood Flow Metab. 2005;25(3):338–47.CrossRefPubMed

Chen XQ, Liu S, Qin LY, Wang CR, Fung YW, Yu AC. Selective regulation of 14-3-3eta in primary culture of cerebral cortical neurons and astrocytes during development. J Neurosci Res. 2005;79(1–2):114–8.CrossRefPubMed

Colucci M, Roccatagliata L, Capello E, Narciso E, Latronico N, Tabaton M, et al. The 14-3-3 protein in multiple sclerosis: a marker of disease severity. Mult Scler. 2004;10(5):477–81.CrossRefPubMed

D'Souza S, Alinauskas K, McCrea E, Goodyer C, Antel JP. Differential susceptibility of human CNS-derived cell populations to TNF-dependent and independent immune-mediated injury. J Neurosci. 1995;15(11):7293–300.PubMed

D'Souza SD, Bonetti B, Balasingam V, Cashman NR, Barker PA, Troutt AB, et al. Multiple sclerosis: Fas signaling in oligodendrocyte cell death. J Exp Med. 1996;184(6):2361–70.PubMedCentralCrossRefPubMed

Dittel BN, Urbania TH, Janeway Jr CA. Relapsing and remitting experimental autoimmune encephalomyelitis in B cell deficient mice. J Autoimmun. 2000;14(4):311–8.CrossRefPubMed

Dong H, Fazzaro A, Xiang C, Korsmeyer SJ, Jacquin MF, McDonald JW. Enhanced oligodendrocyte survival after spinal cord injury in Bax-deficient mice and mice with delayed Wallerian degeneration. J Neurosci. 2003;23(25):8682–91.PubMed

10.

Gajofatto A, Bongianni M, Zanusso G, Benedetti MD, Monaco S. Are cerebrospinal fluid biomarkers useful in predicting the prognosis of multiple sclerosis patients? Int J Mol Sci. 2011;12(11):7960–70.PubMedCentralCrossRefPubMed

11.

Giacomini PS, Levesque IR, Ribeiro L, Narayanan S, Francis SJ, Pike GB, et al. Measuring demyelination and remyelination in acute multiple sclerosis lesion voxels. Arch Neurol. 2009;66(3):375–81.CrossRefPubMed

12.

Hagemeier K, Lurbke A, Hucke S, Albrecht S, Preisner A, Klassen E, et al. Puma, but not noxa is essential for oligodendroglial cell death. Glia. 2013;61(10):1712–23.CrossRefPubMed

13.

Herrero-Herranz E, Pardo LA, Bunt G, Gold R, Stuhmer W, Linker RA. Re-expression of a developmentally restricted potassium channel in autoimmune demyelination: Kv1.4 is implicated in oligodendroglial proliferation. Am J Pathol. 2007;171(2):589–98.PubMedCentralCrossRefPubMed

14.

Kuhlmann T, Lucchinetti C, Zettl UK, Bitsch A, Lassmann H, Bruck W. Bcl-2-expressing oligodendrocytes in multiple sclerosis lesions. Glia. 1999;28(1):34–9.CrossRefPubMed

15.

Ladiwala U, Li H, Antel JP, Nalbantoglu J. p53 induction by tumor necrosis factor-alpha and involvement of p53 in cell death of human oligodendrocytes. J Neurochem. 1999;73(2):605–11.CrossRefPubMed

16.

Lee DH, Geyer E, Flach AC, Jung K, Gold R, Flugel A, et al. Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination. Acta Neuropathol. 2012;123(2):247–58.PubMedCentralCrossRefPubMed

17.

Lee DH, Kubera K, Rosenthal B, Kaltschmidt B, Kaltschmidt C, Gold R, et al. Neuronal NF-kappaB ablation does not influence neuro-axonal degeneration in experimental autoimmune demyelination. J Neuroimmunol. 2012;246(1–2):38–42.CrossRefPubMed

18.

Lindner M, Heine S, Haastert K, Garde N, Fokuhl J, Linsmeier F, et al. Sequential myelin protein expression during remyelination reveals fast and efficient repair after central nervous system demyelination. Neuropathol Appl Neurobiol. 2008;34(1):105–14.PubMed

19.

Linker R, Gold R, Luhder F. Function of neurotrophic factors beyond the nervous system: inflammation and autoimmune demyelination. Crit Rev Immunol. 2009;29(1):43–68.CrossRefPubMed

20.

Linker RA, Kruse N, Israel S, Wei T, Seubert S, Hombach A, et al. Leukemia inhibitory factor deficiency modulates the immune response and limits autoimmune demyelination: a new role for neurotrophic cytokines in neuroinflammation. J Immunol. 2008;180(4):2204–13.CrossRefPubMed

21.

Linker RA, Lee DH, Demir S, Wiese S, Kruse N, Siglienti I, et al. Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis. Brain. 2010;133(Pt 8):2248–63.CrossRefPubMed

22.

Linker RA, Maurer M, Gaupp S, Martini R, Holtmann B, Giess R, et al. CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nat Med. 2002;8(6):620–4.CrossRefPubMed

23.

Linker RA, Rott E, Hofstetter HH, Hanke T, Toyka KV, Gold R. EAE in beta-2 microglobulin-deficient mice: axonal damage is not dependent on MHC-I restricted immune responses. Neurobiol Dis. 2005;19(1–2):218–28.CrossRefPubMed

24.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25(4):402–8.CrossRefPubMed

25.

Magnus T, Chan A, Linker RA, Toyka KV, Gold R. Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: implications for the role of glial cells in the inflamed central nervous system. J Neuropathol Exp Neurol. 2002;61(9):760–6.PubMed

26.

Martinez-Yelamos A, Rovira A, Sanchez-Valle R, Martinez-Yelamos S, Tintore M, Blanco Y, et al. CSF 14-3-3 protein assay and MRI as prognostic markers in patients with a clinically isolated syndrome suggestive of MS. J Neurol. 2004;251(10):1278–9.CrossRefPubMed

27.

Martinez-Yelamos A, Saiz A, Sanchez-Valle R, Casado V, Ramon JM, Graus F, et al. 14-3-3 protein in the CSF as prognostic marker in early multiple sclerosis. Neurology. 2001;57(4):722–4.CrossRefPubMed

28.

Matysiak M, Jurewicz A, Jaskolski D, Selmaj K. TRAIL induces death of human oligodendrocytes isolated from adult brain. Brain. 2002;125(Pt 11):2469–80.CrossRefPubMed

29.

Mc GC, Volckaert T, Wolke U, Sze M, de Rycke R, Waisman A, et al. Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination. J Immunol. 2010;185(12):7646–53.CrossRef

30.

Otto M, Wiltfang J, Cepek L, Neumann M, Mollenhauer B, Steinacker P, et al. Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology. 2002;58(2):192–7.CrossRefPubMed

31.

Ozawa K, Suchanek G, Breitschopf H, Bruck W, Budka H, Jellinger K, et al. Patterns of oligodendroglia pathology in multiple sclerosis. Brain. 1994;117(Pt 6):1311–22.CrossRefPubMed

32.

Prineas JW, Barnard RO, Revesz T, Kwon EE, Sharer L, Cho ES. Multiple sclerosis. Pathology of recurrent lesions. Brain. 1993;116(Pt 3):681–93.CrossRefPubMed

33.

Raine CS. The Norton lecture: a review of the oligodendrocyte in the multiple sclerosis lesion. J Neuroimmunol. 1997;77(2):135–52.CrossRefPubMed

34.

Rena HA, Hagemeier K, Lurbke A, Held J, Friedman H, Peterson A, et al. XIAP protects oligodendrocytes against cell death in vitro but has no functional role in toxic demyelination. Glia. 2012;60(2):271–80.CrossRef

35.

Satoh J, Tabunoki H, Nanri Y, Arima K, Yamamura T. Human astrocytes express 14-3-3 sigma in response to oxidative and DNA-damaging stresses. Neurosci Res. 2006;56(1):61–72.CrossRefPubMed

36.

Satoh J, Yamamura T, Arima K. The 14-3-3 protein epsilon isoform expressed in reactive astrocytes in demyelinating lesions of multiple sclerosis binds to vimentin and glial fibrillary acidic protein in cultured human astrocytes. Am J Pathol. 2004;165(2):577–92.PubMedCentralCrossRefPubMed

37.

Shimada T, Fournier AE, Yamagata K. Neuroprotective function of 14-3-3 proteins in neurodegeneration. Biomed Res Int. 2013;2013:564534.PubMedCentralCrossRefPubMed

38.

Skripuletz T, Hackstette D, Bauer K, Gudi V, Pul R, Voss E, et al. Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain. 2013;136(1):147–67.CrossRefPubMed

39.

Soane L, Cho HJ, Niculescu F, Rus H, Shin ML. C5b-9 terminal complement complex protects oligodendrocytes from death by regulating Bad through phosphatidylinositol 3-kinase/Akt pathway. J Immunol. 2001;167(4):2305–11.CrossRefPubMed

40.

Soane L, Rus H, Niculescu F, Shin ML. Inhibition of oligodendrocyte apoptosis by sublytic C5b-9 is associated with enhanced synthesis of bcl-2 and mediated by inhibition of caspase-3 activation. J Immunol. 1999;163(11):6132–8.PubMed

41.

Sontheimer H, Trotter J, Schachner M, Kettenmann H. Channel expression correlates with differentiation stage during the development of oligodendrocytes from their precursor cells in culture. Neuron. 1989;2(2):1135–45.CrossRefPubMed

42.

Steinacker P, Aitken A, Otto M. 14-3-3 proteins in neurodegeneration. Semin Cell Dev Biol. 2011;22(7):696–704.CrossRefPubMed

43.

Steinacker P, Schwarz P, Reim K, Brechlin P, Jahn O, Kratzin H, et al. Unchanged survival rates of 14-3-3gamma knockout mice after inoculation with pathological prion protein. Mol Cell Biol. 2005;25(4):1339–46.PubMedCentralCrossRefPubMed

44.

Su YW, Hao Z, Hirao A, Yamamoto K, Lin WJ, Young A, et al. 14-3-3sigma regulates B-cell homeostasis through stabilization of FOXO1. Proc Natl Acad Sci U S A. 2011;108(4):1555–60.PubMedCentralCrossRefPubMed

45.

Toft-Hansen H, Füchtbauer L, Owens T. Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease. Glia. 2011;59(1):166–76. doi:10.1002/glia.21088.CrossRefPubMed

46.

Vogt J, Paul F, Aktas O, Muller-Wielsch K, Dorr J, Dorr S, et al. Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis. Ann Neurol. 2009;66(3):310–22.CrossRefPubMed

47.

Voskuhl RR, Peterson RS, Song B, Ao Y, Morales LB, Tiwari-Woodruff S, et al. Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J Neurosci. 2009;29(37):11511–22.PubMedCentralCrossRefPubMed

48.

Wiltfang J, Otto M, Baxter HC, Bodemer M, Steinacker P, Bahn E, et al. Isoform pattern of 14-3-3 proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurochem. 1999;73(6):2485–90.CrossRefPubMed

49.

Wosik K, Antel J, Kuhlmann T, Bruck W, Massie B, Nalbantoglu J. Oligodendrocyte injury in multiple sclerosis: a role for p53. J Neurochem. 2003;85(3):635–44.CrossRefPubMed

50.

Xu Z, Fulop Z, Wu G, Pone EJ, Zhang J, Mai T, et al. 14-3-3 adaptor proteins recruit AID to 5′-AGCT-3′-rich switch regions for class switch recombination. Nat Struct Mol Biol. 2010;17(9):1124–35.PubMedCentralCrossRefPubMed

Title: Role of glial 14-3-3 gamma protein in autoimmune demyelination
Authors: De-Hyung Lee
Petra Steinacker
Silvia Seubert
Tanja Turnescu
Arthur Melms
Arndt Manzel
Markus Otto
Ralf A. Linker
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-015-0381-x

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Role of glial 14-3-3 gamma protein in autoimmune demyelination

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2015

Deferoxamine attenuates lipopolysaccharide-induced neuroinflammation and memory impairment in mice

Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit

Association of brain immune genes with social behavior of inbred mouse strains

Inflammatory mediator release from primary rhesus microglia in response to Borrelia burgdorferi results from the activation of several receptors and pathways

Retraction Note: Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/CX3CR1 signaling

Inflammation and neuronal death in the motor cortex of the wobbler mouse, an ALS animal model