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Karamita M, Barnum C, Möbius W, et al. Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia. JCI Insight. 2017;2(8)doi: 10.1172/jci.insight.87455.
Karamita, M., Barnum, C., Möbius, W., Tansey, M. G., Szymkowski, D. E., Lassmann, H., & Probert, L. (2017). Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia. JCI insight, 2(8), . https://doi.org/10.1172/jci.insight.87455
Karamita, Maria, et al. "Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia." JCI insight vol. 2,8 (2017). doi: https://doi.org/10.1172/jci.insight.87455
Karamita M, Barnum C, Möbius W, Tansey MG, Szymkowski DE, Lassmann H, Probert L. Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia. JCI Insight. 2017 Apr 20;2(8). doi: 10.1172/jci.insight.87455. eCollection 2017 Apr 20. PMID: 28422748; PMCID: PMC5396518.
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JCI Insight. 2017 Apr 20;2(8). doi: 10.1172/jci.insight.87455. eCollection 2017 Apr 20.

Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia.

JCI insight

Maria Karamita, Christopher Barnum, Wiebke Möbius, Malú G Tansey, David E Szymkowski, Hans Lassmann, Lesley Probert

Affiliations

  1. Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
  2. Department of Physiology, Emory University, Atlanta, Georgia, USA.
  3. Department of Neurogenetics, Max Planck Institute for Experimental Medicine, Goettingen, Germany.
  4. Xencor, Monrovia, California, USA.
  5. Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna, Vienna, Austria.

PMID: 28422748 PMCID: PMC5396518 DOI: 10.1172/jci.insight.87455

Abstract

Multiple sclerosis (MS) is an inflammatory CNS demyelinating disease in which remyelination largely fails. Transmembrane TNF (tmTNF) and TNF receptor 2 are important for remyelination in experimental MS models, but it is unknown whether soluble TNF (solTNF), a major proinflammatory factor, is involved in regeneration processes. Here, we investigated the specific contribution of solTNF to demyelination and remyelination in the cuprizone model. Treatment with XPro1595, a selective inhibitor of solTNF that crosses the intact blood-brain barrier (BBB), in cuprizone-fed mice did not prevent toxin-induced oligodendrocyte loss and demyelination, but it permitted profound early remyelination due to improved phagocytosis of myelin debris by CNS macrophages and prevented disease-associated decline in motor performance. The beneficial effects of XPro1595 were absent in TNF-deficient mice and replicated in tmTNF-knockin mice, showing that tmTNF is sufficient for the maintenance of myelin and neuroprotection. These findings demonstrate that solTNF inhibits remyelination and repair in a cuprizone demyelination model and suggest that local production of solTNF in the CNS might be one reason why remyelination fails in MS. These findings also suggest that disinhibition of remyelination by selective inhibitors of solTNF that cross the BBB might represent a promising approach for treatment in progressive MS.

Keywords: Autoimmunity; Therapeutics

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