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CNTF is a major protective factor in demyelinating CNS disease: A neurotrophic cytokine as modulator in neuroinflammation

Nature Medicine volume 8, pages 620–624 (2002)Cite this article

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS)1. So far, immunological mechanisms responsible for demyelination have been the focus of interest2. However, mechanisms regulating axon maintenance as well as glial precursor-cell proliferation and oligodendrocyte survival might also influence disease outcome3. The cytokine ciliary neurotrophic factor (CNTF), which was originally identified as a survival factor for isolated neurons, promotes differentiation, maturation and survival of oligodendrocytes4,5,6. To investigate the role of endogenous CNTF in inflammatory demyelinating disease, we studied myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in CNTF-deficient and wild-type C57BL/6 mice. Disease was more severe in CNTF-deficient mice and recovery was poor, with a 60% decrease in the number of proliferating oligodendrocyte precursor cells (OPCs) and a more than 50% increase in the rate of oligodendrocyte apoptosis. In addition, vacuolar dystrophy of myelin and axonal damage were more severe in CNTF-deficient mice. These specific pathological features could be prevented by treatment with an antiserum against tumor necrosis factor-α, suggesting that endogenous CNTF may counterbalance this effect of TNF-α (ref. 7). Here we identify a factor that modulates, in an inflammatory environment, glial cell survival and is an outcome determinant of EAE.

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Figure 1: CNTF deficiency influences disease onset and long-term course from EAE.
Figure 2: CNTF influences proliferation and survival of oligodendrocyte lineage cells under pro-inflammatory conditions.
Figure 3: Endogenous CNTF protects integrity of myelin sheaths and associated axons.

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Acknowledgements

We thank V.T. Wörtmann, G. Köllner, H. Brünner and D. Seemann for expert technical assistance; T. Hartung for the gift of neutralizing anti-TNFα antiserum; and M. Stienekemeier and M. Giraldo for contributions in the early phase of the project. This work was supported by the Deutsche Forschungsgemeinschaft (DFG), SFB 581, TPA1 and TPB3 and funds from the state of Bavaria.

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Authors and Affiliations

  1. Department of Neurology, Clinical Research Group for Multiple Sclerosis, Julius-Maximilians-Universität Würzburg, Würzburg, Germany

    Ralf A. Linker, Mathias Mäurer, Stefanie Gaupp, Ralf Giess, Peter Rieckmann, Klaus V. Toyka & Ralf Gold

  2. Department of Neurology, Section of Developmental Neurobiology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany

    Rudolf Martini

  3. Department of Clinical Neurobiology, Julius-Maximilians-Universität, Würzburg, Germany

    Bettina Holtmann & Michael Sendtner

  4. Brain Research Institute, Vienna, Austria

    Hans Lassmann

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  1. Ralf A. Linker
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Linker, R., Mäurer, M., Gaupp, S. et al. CNTF is a major protective factor in demyelinating CNS disease: A neurotrophic cytokine as modulator in neuroinflammation. Nat Med 8, 620–624 (2002). https://doi.org/10.1038/nm0602-620

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