c-Jun N-Terminal Kinase as a Therapeutic Target in Experimental Autoimmune Encephalomyelitis

Maud Bagnoud, Myriam Briner, Jana Remlinger, Ivo Meli, Sara Schuetz, Maximilian Pistor, Anke Salmen, Andrew Chan, Robert Hoepner

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

c-Jun N-terminal kinase (JNK) is upregulated during multiple sclerosis relapses and at the peak of experimental autoimmune encephalomyelitis (EAE). We aim to investigate the effects of pharmacological pan-JNK inhibition on the course of myelin oligodendrocyte glycoprotein (MOG35-55) EAE disease using in vivo and in vitro experimental models. EAE was induced in female C57BL/6JRj wild type mice using MOG35-55. SP600125 (SP), a reversible adenosine triphosphate competitive pan-JNK inhibitor, was then given orally after disease onset. Positive correlation between SP plasma and brain concentration was observed. Nine, but not three, consecutive days of SP treatment led to a significant dose-dependent decrease of mean cumulative MOG35-55 EAE severity that was associated with increased mRNA expression of interferon gamma (INF-γ) and tumor necrosis factor alpha (TNF-α) in the spinal cord. On a histological level, reduced spinal cord immune cell-infiltration predominantly of CD3+ T cells as well as increased activity of Iba1+ cells were observed in treated animals. In addition, in vitro incubation of murine and human CD3+ T cells with SP resulted in reduced T cell apoptosis and proliferation. In conclusion, our study demonstrates that pharmacological pan-JNK inhibition might be a treatment strategy for autoimmune central nervous system demyelination.

Original languageEnglish
Article number2151
JournalCells
Volume9
Issue number10
DOIs
StatePublished - 23 Sep 2020
Externally publishedYes

Keywords

  • MAPK
  • SP600125
  • immunotherapy
  • mitogen-activated protein kinases
  • multiple sclerosis
  • neuroinflammation

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