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

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.

Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness

“…In addition, increased JNK phosphorylation, indicative of JNK signalling, was found in the acute disease phase of experimental autoimmune encephalomyelitis rats, an animal model mimicking neuroinflammation in MS [ 59 ]. Given the importance of the JNK pathway in pathological conditions, pan-JNK inhibition has been proposed as a novel treatment strategy for diseases associated with neurodegeneration and neuroinflammation [ 60 , 61 ] and, thus, might also be of advantage in the context of X-ALD.…”

In Vivo and In Vitro Evidence for an Interplay between the Glucocorticoid Receptor and the Vitamin D Receptor Signaling

“…Experimental autoimmune encephalomyelitis: Active MOG 35–55 EAE was induced in 8–12 weeks-old female GR wt and GR lck mice following our previously described protocol [ 23 , 26 ]. Briefly, animals were immunized by subcutaneous injection of 100 µg MOG 35–55 peptide (Institute of Medical Immunology, Charité, Berlin, Germany) in PBS (VWR, PA, USA) emulsified in complete Freund’s adjuvant containing 100 µg mycobacterium tuberculosis (Difco, MA, USA), followed by 200 ng pertussis toxin (Quadratech, Eastbourne, UK, intraperitoneal (i.p.)…”

The Role of the Dysregulated JNK Signaling Pathway in the Pathogenesis of Human Diseases and Its Potential Therapeutic Strategies: A Comprehensive Review

“…Zhang et al found that JNK was overactivated in chronic active MS plaques [134]. Bagnoud et al also found that the phosphorylated JNK is increased during demyelination-triggered MS [135]. During the progression of MS, the phosphorylation of JNK by ASK1 plays critical roles in multiple processes, such as oligodendrocyte destruction, demyelination, neuroinflammation, immune dysregulation through T cell activation (T cell apoptosis), and oxidative damage.…”

“…In addition to the TLR (Toll-like receptor), other factors, including reactive oxygen species (ROS), oxidative stress, and inflammation, can activate ASK1 during MS progression [137]. These reports indicate that the over-activated ASK1-MKK4/7-JNK signaling axis plays a critical role in the pathogenesis of MS; that is, deregulated JNK signaling contributes to MS progression [134,135,137].…”