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

Cells. 2020 Sep 23;9(10):2154. doi: 10.3390/cells9102154.

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.

Keywords: MAPK; SP600125; immunotherapy; mitogen-activated protein kinases; multiple sclerosis; neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mice, Inbred C57BL
  • Multiple Sclerosis / metabolism*
  • Myelin-Oligodendrocyte Glycoprotein / metabolism
  • T-Lymphocytes / immunology

Substances

  • Cytokines
  • Myelin-Oligodendrocyte Glycoprotein
  • JNK Mitogen-Activated Protein Kinases