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

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

doi:10.3390/cells9102154

Maud Bagnoud, Maximilian Pistor + Show 7 more

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https://doi.org/10.3390/cells9102154

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Journal: Cells	Publication Date: Sep 23, 2020
Citations: 11	License type: CC BY 4.0

Affiliation: University Hospital of Bern, University of Bern

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.

Highlights

Multiple sclerosis (MS) is an inflammatory and degenerative disorder of the central nervous system (CNS) [1]
30 mg/kg/day-treated acute MOG35-55 EAE-diseased mice was of 3.35 nM (SEM 0.45, n = 5), whereas the mean SP brain concentration was of 8.62 nM (SEM 2.46, n = 4)
Using two different in vivo treatment regimens, our study demonstrated that pharmacological pan-Jun N-terminal kinase (JNK) inhibition ameliorates MOG35-55 EAE disease course when administered after disease onset over nine consecutive days in a therapeutic setting

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory and degenerative disorder of the central nervous system (CNS) [1]. Mitogen-activated protein kinases (MAPKs) have been shown to be involved in the regulation of cytokine gene expression, immune cell differentiation, neuronal-cell-death pathways and regulation of astrocyte inflammatory genes [2,3]. They might influence both pathomechanisms of MS; neuroinflammation and degeneration. MAPKs are divided into three subfamilies: The c-Jun N-terminal kinases (JNKs), the extracellular signal-regulated kinases (ERKs) and the p38 mitogen-activated protein kinases (p38) [4]. It was demonstrated that cytokines, hormones or morphogenic factors were able to activate the c-Jun N-terminal kinase (JNK) pathway [6]

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