Role of glial 14-3-3 gamma protein in autoimmune demyelination.

De-Hyung Lee,Tanja Turnescu,Silvia Seubert,Arndt Manzel,Arthur Melms,Petra Steinacker,Markus Otto,Ralf A Linker

doi:10.1186/s12974-015-0381-x

Abstract

BackgroundThe family of 14-3-3 proteins plays an important role in the regulation of cell survival and death. Here, we investigate the role of the 14-3-3 gamma (14-3-3 γ) subunit for glial responses in autoimmune demyelination.MethodsExpression of 14-3-3 γ in glial cell culture was investigated by reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. 14-3-3 γ knockout mice were subjected to murine myelin oligodendrocyte-induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of multiple sclerosis (MS).ResultsExpression studies in cell culture confined expression of 14-3-3 γ to both, oligodendrocytes (OL) and astrocytes. RT-PCR analysis revealed an increased expression of 14-3-3 γ mRNA in the spinal cord during the late chronic phase of MOG-EAE. At that stage, EAE was more severe in 14-3-3 γ knockout mice as compared to age- and gender-matched controls. Histopathological analyses on day 56 post immunization (p.i.) revealed significantly enhanced myelin damage as well as OL injury and secondary, an increase in axonal injury and gliosis in 14-3-3 γ −/− mice. At the same time, deficiency in 14-3-3 γ protein did not influence the immune response. Further histological studies revealed an increased susceptibility towards apoptosis in 14-3-3 γ-deficient OL in the inflamed spinal cord.ConclusionThese data argue for a pivotal role of 14-3-3 γ-mediated signalling pathways for OL protection in neuroinflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0381-x) contains supplementary material, which is available to authorized users.

Highlights

The family of 14-3-3 proteins plays an important role in the regulation of cell survival and death
reverse transcription polymerase chain reaction (RT-PCR) for expression of 14-3-3 γ was performed in purified astrocytes and O4 sorted oligodendroglial precursor cells (OPC)
Our study reveals that 14-3-3 γ protein is present in oligodendroglial cells and that 14-3-3 γ deficiency leads to more severe chronic EAE with enhanced demyelination, OL loss, and increased OL apoptosis

Summary

Introduction

The family of 14-3-3 proteins plays an important role in the regulation of cell survival and death. We investigate the role of the 14-3-3 gamma (14-3-3 γ) subunit for glial responses in autoimmune demyelination. Several factors were identified which govern OL susceptibility after an inflammatory attack in the CNS Such factors comprise neurotrophic cytokines like ciliary neurotrophic factor, leukemia inhibitory factor, or other neurotrophic factors [2, 19, 22]. To assess the role of 14-3-3 proteins in autoimmune demyelination, we employ mice deficient for the 14-3-3 gamma subunit (14-3-3 γ −/− mice). If not challenged, these mice display a normal anatomy and behavior. 14-3-3 γ deficiency may impair the recruitment of activationinduced cytidine deaminase to immunoglobulin H switch regions and is involved in class switch DNA recombination, a mechanism that diversifies the biological antibody response [50]

Methods

Results

Discussion

Conclusion