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Lipopolysaccharide induces human olfactory ensheathing glial apoptosis by promoting mitochondrial dysfunction and activating the JNK-Bnip3-Bax pathway.

ABSTRACT: Olfactory ensheathing glia (OEG) play an important role in regulating the regeneration of an injured nervous system. However, chronic inflammation damage reduces the viability of OEG via poorly understood mechanisms. We aimed to investigate the pathological responses of OEG in response to LPS-mediated inflammation stress in vitro. The results indicated that lipopolysaccharide (LPS) treatment significantly reduced the viability of OEG in a dose-dependent fashion. Mechanistically, LPS stimuli induced mitochondrial oxidative damage, mitochondrial fragmentation, mitochondrial metabolism disruption, and mitochondrial apoptosis activation. Furthermore, we verified that LPS modulated mitochondrial apoptosis by promoting Bax upregulation, and this process was regulated by the JNK-Bnip3 pathway. Inhibition of the JNK-Bnip3 pathway prevented LPS-mediated Bax activation, thus attenuating OEG apoptosis. Altogether, our data illustrated that LPS-mediated inflammation injury evoked mitochondrial abnormalities in OEG damage via the JNK-Bnip3-Bax pathway. This finding provides a potential target to protect OEG against chronic inflammation stress.

SUBMITTER: He M

PROVIDER: S-EPMC6363633 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Lipopolysaccharide induces human olfactory ensheathing glial apoptosis by promoting mitochondrial dysfunction and activating the JNK-Bnip3-Bax pathway.

He Maowei M Xiang Zimin Z Xu Libin L Duan Yanting Y Li Fangqin F Chen Jianmei J

Cell stress & chaperones 20181029 1

Olfactory ensheathing glia (OEG) play an important role in regulating the regeneration of an injured nervous system. However, chronic inflammation damage reduces the viability of OEG via poorly understood mechanisms. We aimed to investigate the pathological responses of OEG in response to LPS-mediated inflammation stress in vitro. The results indicated that lipopolysaccharide (LPS) treatment significantly reduced the viability of OEG in a dose-dependent fashion. Mechanistically, LPS stimuli indu ...[more]

PMID: 30374881

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Project description:The gradual deterioration following central nervous system (CNS) injuries or neurodegenerative disorders is usually accompanied by infiltration of degenerated and apoptotic neural tissue debris. A rapid and efficient clearance of these deteriorated cell products is of pivotal importance in creating a permissive environment for regeneration of those damaged neurons. Our recent report revealed that the phagocytic activity of olfactory ensheathing cells (OECs) can make a substantial contribution to neuronal growth in such a hostile environment. However, little is known about how to further increase the ability of OECs in phagocytosing deleterious products. Here, we used an in vitro model of primary cells to investigate the effects of lipopolysaccharide (LPS) and curcumin (CCM) co-stimulation on phagocytic activity of OECs and the possible underlying mechanisms. Our results showed that co-stimulation using LPS and CCM can significantly enhance the activation of OECs, displaying a remarkable up-regulation in chemokine (C-X-C motif) ligand 1, chemokine (C-X-C motif) ligand 2, tumor necrosis factor-α, and Toll-like receptor 4, increased OEC proliferative activity, and improved phagocytic capacity compared with normal and LPS- or CCM-treated OECs. More importantly, this potentiated phagocytosis activity greatly facilitated neuronal growth under hostile culture conditions. Moreover, the up-regulation of transglutaminase-2 and phosphatidylserine receptor in OECs activated by LPS and CCM co-stimulation are likely responsible for mechanisms underlying the observed cellular events, because cystamine (a specific inhibitor of transglutaminase-2) and neutrophil elastase (a cleavage enzyme of phosphatidylserine receptor) can effectively abrogate all the positive effects of OECs, including phagocytic capacity and promotive effects on neuronal growth. This study provides an alternative strategy for the repair of traumatic nerve injury and neurologic diseases with the application of OECs in combination with LPS and CCM.

Project description:ObjectiveThe aim of this study was to investigate the pro-angiogenic potential of olfactory ensheathing cells (OECs) activated by curcumin (CCM) and lipopolysaccharide (LPS) and the possible underlying mechanisms.MethodsVascular endothelial cells or tissues were cultured and treated with conditioned medium (CM) extracted from activated OECs activated through the addition of LPS and CCM or unactivated controls. Concomitantly, the pro-angiogenic potential of OECs was assessed in vitro by aortic ring sprouting assay, endothelial wound healing assay, CCK-8 assay, and tube formation assay. Subsequently, the OECs were co-cultured with endothelial cells to evaluate their promoting effect on endothelial cell proliferation and migration following a mechanical scratch. Moreover, the spinal cord injury (SCI) model in rats was established, and the number of endothelial cells and vascular structure in the injured area after SCI was observed with OEC transplantation. Finally, the underlying mechanism was investigated by western blot analysis of phosphorylated kinase expression with or without the MK-2206 (Akt-inhibitor).ResultThe present results showed that the activated OECs can effectively promote vascular endothelial cells' proliferation, migration, and vessel-like structure formation. Strikingly, several pro-angiogenic growth factors such as VEGF-A and PDGF-AA, which facilitate vessel formation, were found to be significantly elevated in CM. In addition, the PI3K/Akt signaling pathway was found to be involved in pro-angiogenic events caused by activated OEC CM, displaying higher phosphorylation levels in cells. In contrast, the delivery of MK2206 can effectively abrogate all the positive effects.ConclusionsOECs activated by LPS and CCM have a pro-angiogenic effect and can effectively promote angiogenesis and improve the microenvironment at the injury site when transplanted in the injured spinal cord. This potentiated ability of OECs to provide pro-angiogenic effects is likely mediated through the PI3K/Akt pathway.

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Lipopolysaccharide induces human olfactory ensheathing glial apoptosis by promoting mitochondrial dysfunction and activating the JNK-Bnip3-Bax pathway.

Publications

Lipopolysaccharide induces human olfactory ensheathing glial apoptosis by promoting mitochondrial dysfunction and activating the JNK-Bnip3-Bax pathway.

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