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A Role for Neuronal NF-κB in Suppressing Neuroinflammation and Promoting Neuroprotection in the CNS

  • Mary Emmanouil
  • Era Taoufik
  • Vivian Tseveleki
  • Sotiris-Spyros Vamvakas
  • Lesley Probert
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)

Abstract

Nuclear factor-κB (NF-κB) signaling plays a crucial role during inflammatory, demyelinating disease and that becomes evident through opposing proinflammatory and neuroprotective functions that depend on the different cell types in which it is activated. The role of NF-κB activation specifically in neurons during pathological conditions in the central nervous system (CNS) needs to be elucidated. We applied conditional gene targeting in C57Bl6 mice to delete the inhibitor of NF-κB kinase β (IKKβ), a kinase essential for activation of the canonical NF-κB pathway, specifically in CNS neurons and immunized them with MOG35−55 peptide to induce experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. Mice lacking neuronal IKKβ (nIKKβKO) developed a more severe, non-resolving disease compared to control mice with increased axonal damage during the chronic phase. nIKKβKO mice in the early chronic phase of disease showed significantly reduced levels of neuroprotective molecules and enhanced expression of immune mediators that are known to be important for EAE pathogenesis compared to control mice. Additionally, increased proportions of CD4+ and CD4+IFNγ+ cells and decreased proportion of NK1.1+ cells in nIKKβKO mice reveal differences in CNS-infiltrating monocytes between the two groups. Our results show that NF-κB in CNS neurons plays a critical role in modulating the severity of autoimmune demyelinating disease, not only by enhancing neuroprotection but also by suppressing CNS immune responses, and emphasizes the importance of neuroprotective strategies for the treatment of multiple sclerosis.

Keywords

Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Demyelinating Disease Experimental Autoimmune Encephalomyelitis Mouse Central Nervous System Inflammation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We wish to thank Michael Karin for providing conditional IKKβ mutant mice and Hans Lassmann for performing all the neuropathological analyses. This work was supported in part by the Hellenic Secretariat of Research and Technology, ΠENEΔ 03EΔ827 grant, by the 6th Framework Program of the European Union, NeuroproMiSe, LSHM-CT-2005-018637, and by a short-term scientific mission grant to Vivian Tseveleki by the COST Action NEURINFNET (BM0603).

References

  1. 1.
    Wekerle H (1993) Experimental autoimmune encephalomyelitis as a model of immune-mediated CNS disease. Curr Opin Neurobiol 3(5):779–784CrossRefPubMedGoogle Scholar
  2. 2.
    Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129(8):1953–1971CrossRefPubMedGoogle Scholar
  3. 3.
    DeAngelis T, Lublin F (2008) Neurotherapeutics in multiple sclerosis: novel agents and emerging treatment strategies. Mt Sinai J Med 75(2):157–167CrossRefPubMedGoogle Scholar
  4. 4.
    Hilliard B, Samoilova EB, Liu TS, Rostami A, Chen Y (1999) Experimental autoimmune encephalomyelitis in NF-kappa B-deficient mice: roles of NF-kappa B in the activation and differentiation of autoreactive T cells. J Immunol 163(5):2937–2943PubMedGoogle Scholar
  5. 5.
    Greve B, Weissert R, Hamdi N, Bettelli E, Sobel RA, Coyle A, Kuchroo VK, Rajewsky K, Schmidt-Supprian M (2007) I kappa B kinase 2/beta deficiency controls expansion of autoreactive T cells and suppresses experimental autoimmune encephalomyelitis. J Immunol 179(1):179–185PubMedGoogle Scholar
  6. 6.
    van Loo G, De Lorenzi R, Schmidt H, Huth M, Mildner A, Schmidt-Supprian M, Lassmann H, Prinzi MR, Pasparakis M (2006) Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat Immunol 7:954–961CrossRefPubMedGoogle Scholar
  7. 7.
    Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI, Dvoriantchikova G, Ivanov D, Nathanson L, Barnum SR, Bethea JR (2009) Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J Immunol 182:2628–2640CrossRefPubMedGoogle Scholar
  8. 8.
    Lawrence T, Gilroy DW, Colville-Nash PR, Willoughby DA (2001) Possible new role for NF-kappaB in the resolution of inflammation. Nat Med 7(12):1291–1297CrossRefPubMedGoogle Scholar
  9. 9.
    Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003) NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 6(10):1072–1078CrossRefPubMedGoogle Scholar
  10. 10.
    Albensi BC, Mattson MP (2000) Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse 35(2):151–159CrossRefPubMedGoogle Scholar
  11. 11.
    Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L, Prullage M, Pfeiffer J, Lindecke A, Staiger V, Israel A, Kaltschmidt C, Memet S (2006) NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. Mol Cell Biol 26(8):2936–2946CrossRefPubMedGoogle Scholar
  12. 12.
    Youssef S, Steinman L (2006) At once harmful and beneficial: the dual properties of NF-kappaB. Nat Immunol 7(9):901–902CrossRefPubMedGoogle Scholar
  13. 13.
    Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(2):S81–S96CrossRefPubMedGoogle Scholar
  14. 14.
    Karin M, Lin A (2002) NF-kappaB at the crossroads of life and death. Nat Immunol 3(3):221–227CrossRefPubMedGoogle Scholar
  15. 15.
    Park JM, Greten FR, Li ZW, Karin M (2002) Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297(5589):2048–2051CrossRefPubMedGoogle Scholar
  16. 16.
    Li ZW, Omori SA, Labuda T, Karin M, Rickert RC (2003) IKK beta is required for peripheral B cell survival and proliferation. J Immunol 170(9):4630–4637PubMedGoogle Scholar
  17. 17.
    Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V, Rossi-Arnaud C, Lipp HP, Bonhoeffer T, Klein R (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24(2):401–414CrossRefPubMedGoogle Scholar
  18. 18.
    Emmanouil M, Taoufik E, Tseveleki V, Vamvakas SS, Tselios T, Karin M, Lassmann H, Probert L (2009) Neuronal IκB Kinase β protects mice from autoimmune encephalomyelitis by mediating neuroprotective and immunosuppressive effects in the CNS. J Immunol 183:7877–7889CrossRefPubMedGoogle Scholar
  19. 19.
    Taoufik E, Valable S, Muller GJ, Roberts ML, Divoux D, Tinel A, Voulgari-Kokota A, Tseveleki V, Altruda F, Lassmann H, Petit E, Probert L (2007) FLIP(L) protects neurons against in vivo ischemia and in vitro glucose deprivation-induced cell death. J Neurosci 27(25):6633–6646CrossRefPubMedGoogle Scholar
  20. 20.
    Kreuz S, Siegmund D, Scheurich P, Wajant H (2001) NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol Cell Biol 21:3964–3973CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Mary Emmanouil
    • 1
  • Era Taoufik
    • 1
  • Vivian Tseveleki
    • 1
  • Sotiris-Spyros Vamvakas
    • 1
  • Lesley Probert
    • 1
  1. 1.Laboratory of Molecular GeneticsHellenic Pasteur InstituteAthensGreece

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