Lymphotoxin β receptor (LtβR): Dual roles in demyelination and remyelination and successful therapeutic intervention using LtβR-Ig protein

Sheila R. Plant, Heather A. Iocca, Ying Wang, J. Cameron Thrash, Brian P. O'Connor, Heather A. Arnett, Yang Xin Fu, Monica J. Carson, Jenny P.Y. Ting

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Inflammation mediated by macrophages is increasingly found to play a central role in diseases and disorders that affect a myriad of organs, prominent among these are diseases of the CNS. The neurotoxicant-induced, cuprizone model of demyelination is ideally suited for the analysis of inflammatory events. Demyelination on exposure to cuprizone is accompanied by predictable microglial activation and astrogliosis, and, after cuprizone withdrawal, this activation reproducibly diminishes during remyelination. This study demonstrates enhanced expression of lymphotoxin β receptor (LtβR) during the demyelination phase of this model, and LtβR is found in areas enriched with microglial and astroglial cells. Deletion of the LtβRgene (LtβR-/-) resulted in a significant delay in demyelination but also a slight delay in remyelination. Inhibition of LtβR signaling by an LtβR-Ig fusion decoy protein successfully delayed demyelination in wild-type mice. Unexpectedly, this LtβR-Ig decoy protein dramatically accelerated the rate of remyelination, even after the maximal pathological disease state had been reached. This strongly indicates the beneficial role of LtβR-Ig in the delay of demyelination and the acceleration of remyelination. The discrepancy between remyelination rates in these systems could be attributed to developmental abnormalities in the immune systems of LtβR-/- mice. These findings bode well for the use of an inhibitory LtβR-Ig as a candidate biological therapy in demyelinating disorders, because it is beneficial during both demyelination and remyelination.

Original languageEnglish (US)
Pages (from-to)7429-7437
Number of pages9
JournalJournal of Neuroscience
Volume27
Issue number28
DOIs
StatePublished - Jul 11 2007

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Keywords

  • Cuprizone
  • Demyelination
  • Glia
  • Ltαβ
  • LtβR
  • Therapy

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Plant, S. R., Iocca, H. A., Wang, Y., Thrash, J. C., O'Connor, B. P., Arnett, H. A., Fu, Y. X., Carson, M. J., & Ting, J. P. Y. (2007). Lymphotoxin β receptor (LtβR): Dual roles in demyelination and remyelination and successful therapeutic intervention using LtβR-Ig protein. Journal of Neuroscience, 27(28), 7429-7437. https://doi.org/10.1523/JNEUROSCI.1307-07.2007