Knockdown of interleukin-10 induces the redistribution of sigma1-receptor and increases the glutamate-dependent NADPH-oxidase activity in mouse brain neuronsReportar como inadecuado




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Biological Research

, 48:55

First Online: 09 October 2015Received: 24 July 2015Accepted: 01 October 2015DOI: 10.1186-s40659-015-0048-1

Cite this article as: Koriauli, S., Natsvlishvili, N., Barbakadze, T. et al. Biol Res 2015 48: 55. doi:10.1186-s40659-015-0048-1

Abstract

BackgroundIn the central nervous system, interleukin-10 IL-10 provides trophic and survival effects directly on neurons, modulates neurite plasticity, and has a pivotal importance in the neuronal regeneration in neurodegenerative and neuroinflammatory conditions. This cytokine is primarily produced by glial cells and has beneficial effects on the neuronal viability. However, the mechanisms of IL-10-elicited neuroprotection are not clear.

ResultsMembrane preparations, isolated from wild-type Wt and IL-10 knockout KO mice brain were used in this study. It has been shown that compared to wild-type mice, in IL-10 KO mice brain, the amount of immunoglobulin binding protein BiP is greatly increased, whereas the content of sigma receptor-1 SigR1 is not changed significantly. Co-immunoprecipitation experiments have shown that the association of SigR1 with small GTPase Rac1 Ras-related C3 botulinum toxin substrate 1, NR2B subunit of NMDA-receptor NMDAR and inositol-3-phosphate receptor IP3R is higher in the IL-10 KO mice brain than in the Wt mice brain. Besides, we have found that either glutamate or sigma ligands, separately or together, do not change glutamate-induced NADPH-oxidase NOX activity in Wt-type mice brain membrane preparations, whereas in IL-10 KO mice high concentration of glutamate markedly increases the NOX-dependent production of reactive oxygen species ROS. Glutamate-dependent ROS production was decreased to the normal levels by the action of sigma-agonists.

ConclusionsIt has been concluded that IL-10 deprivation, at least in part, can lead to the induction of ER-stress, which causes BiP expression and SigR1 redistribution between components of endoplasmic reticulum ER and plasma membrane. Moreover, IL-10 deficiency can change the specific organization of NMDAR, increasing the surface expression of SigR1-sensitive NR2B-containing NMDAR. In these conditions, glutamate-dependent ROS production is greatly increased leading to the initiation of apoptosis. In this circumstances, sigma-ligands could play a preventive role against NMDA receptor-mediated excitotoxicity.

KeywordsInterleukin-10 NMDA-receptor NR2B subunit NADPH-oxidase Rac1 BiP SigR1 ER stress Neurodegeneration Neuroinflammation AbbreviationsIL-10Interleukin-10

WtWild type mice

KOKnockout mice

BiPImmunoglobulin binding protein

SigR1Sigma receptor-1

IP3RInositol-3-phosphate receptor

NOXNADPH-oxidase

ROSReactive oxygen species

EREndoplasmic reticulum

Rac1Ras-related C3 botulinum toxin substrate 1

MAMMitochondria-associated membrane

nNOSNeuronal nitric oxide synthase

NONitric oxide

PSD95Postsynaptic density protein 95

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Autor: S. Koriauli - N. Natsvlishvili - T. Barbakadze - D. Mikeladze

Fuente: https://link.springer.com/



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