Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways

Park, Junghyung; Min, Ju-Sik; Kim, Bokyung; Chae, Unbin; Yun, Jong Won; Choi, Myung‐Sook; Kong, Il‐Keun; Chang, Kyu‐Tae; Lee, Dong Seok

doi:10.1016/j.neulet.2014.10.016

Cited by 425 publications

(279 citation statements)

References 26 publications

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“…Furthermore, it also increases lipid peroxidation and free radicals such as nitric oxide (NO) [38]. LPS induced ROS production in multiple cell types, and the mechanism included LPS-stimulated mitochondrial fission and reduced PPARγ expression [39, 40]. Herein, we showed that both high glucose and LPS administration induced extremely high level of ROS production.…”

Section: Discussionmentioning

confidence: 99%

Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice

Yang

Dong

et al. 2017

Cell Physiol Biochem

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Background/Aims: Sepsis is a common disease that continues to increase in prevalence worldwide, and diabetes mellitus may make the situation worse. This study was designed to determine the role of Liver Kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in diabetic mice complicated with systemic endotoxemia. Methods: The effects of LKB1/AMPK signaling pathway activation on endotoxemia were investigated in streptozotocin induced diabetic mice (STZ-mice) and db/db diabetic mice. Primary peritoneal macrophages and human umbilical vein endothelial cells (HUVECs) monolayers were simultaneously stimulated by both high glucose and LPS and used as a model to investigate the potential molecular mechanisms in vitro. Results: After treatment with LPS, high glucose or both LPS and high glucose, phosphor-AMPK expression was decreased, and moreover, AMPK activation by metformin treatment alleviated the decrease in phosphor-AMPK expression in HUVECs and macrophages as well as in lung tissue. Furthermore, both LPS and high glucose co-treatment decreased LKB1 and phosphor-AMPK expression via enhanced oxidative stress response, and importantly, LKB1 overexpression mediated by adenovirus inhibited the decrease in phosphor-AMPK expression in macrophages and HUVECs. AMPK activation by metformin administration improved the survival of STZ-induced diabetic mice and db/db diabetic mice, which was associated with reduced lung endothelial hyperpermeability and systemic inflammatory response. Furthermore, the permeability of HUVECs monolayers induced by both high glucose and LPS stimulation was also alleviated by AMPK activation, which was partly via suppression of VE-cadherin phosphorylation. Conclusion: These data demonstrated that LKB1/AMPK signaling pathway activation improved the survival of diabetic mice complicated with endotoxemia. Thus, LKB1/AMPK signaling pathway may serve as a potentially useful therapeutic target for severe infection in diabetic patients.

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Section: Discussionmentioning

confidence: 99%

Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice

Yang

Dong

et al. 2017

Cell Physiol Biochem

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“…It has been demonstrated that mitogen-activated protein kinase (MAPK) pathways are activated by upregulation of intracellular ROS (12)(13)(14). P38 and ERK1/2 are important members of the MAPK family, which regulates cell growth and apoptosis (15)(16)(17).…”

Section: P38 and Erk1/2 Signaling Are Involved In Ua-induced Apoptosismentioning

confidence: 99%

Nox4 has a crucial role in uric acid-induced oxidative stress and apoptosis in renal tubular cells

Sheng

Liu

et al. 2016

Molecular Medicine Reports

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Abstract. The purpose of the present study was to evaluate the effects of uric acid in promoting tubular cell apoptosis and verify the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4)-induced oxidative stress in this process. HK-2 cells were used as a human proximal tubular cell model and co-cultured with various concentrations of uric acid with or without pre-treatment with the Nox4 inhibitor diphenylene iodonium (DPI). The apoptotic rate and the amount of reactive oxygen species (ROS) were examined by flow cytometry. Furthermore, levels of Nox4, phosphorylated (p)-P38, p-extracellular signal-regulated kinase (ERK), B-cell lymphoma 2 (Bcl-2) and Bcl-2-extra large (Bax) were detected by western blot analysis. The results showed that treatment with uric acid decreased HK-2 cell viability and promoted apoptosis in a dose-dependent manner. This was paralleled with an upregulation of Nox4 as well as ROS overproduction, which activated the phosphorylation of P38/ERK and caused an imbalance of Bax/Bcl-2 in HK-2 cells. Of note, inhibition of Nox4 with DPI prevented uric acid-induced cell injury by suppressing ROS generation and P38/ERK activation. In conclusion, it was demonstrated that elevated uric acid promoted ROS-induced tubular cell apoptosis by upregulating Nox4 expression. The present study therefore provided possible mechanisms and a potential therapeutic target of uric acid-induced chronic kidney disease.

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“…Activation of the immune response by pathogen associated molecular patterns (PAMPs) is reliant on mitochondrial mechanisms for induction of pro-inflammatory cytokines [29–33]. These mechanisms are most prevalent in microglia, antigen-presenting neuroglia that scavenge the brain for insults and mediate several neuroinflammatory signaling events.…”

Section: Introductionmentioning

confidence: 99%

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

et al. 2018

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Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus that is highly infectious as an aerosol and can result in an encephalitic phenotype in infected individuals. VEEV infections are known to be associated with robust inflammation that eventually contributes to neurodegenerative phenotypes. In this study, we utilize the TC-83 strain of VEEV, which is known to induce the expression of IL-6, IL-8, and other pro-inflammatory cytokines. We had previously demonstrated that TC-83 infection resulted in changes in mitochondrial function, eventually resulting in mitophagy. In this manuscript, we provide data that links upstream mitochondrial dysfunction with downstream pro-inflammatory cytokine production in the context of microglia and astrocytoma cells. We also provide data on the role of bystander cells, which significantly contribute to the overall inflammatory load. Use of a mitochondrial-targeted antioxidant, mitoquinone mesylate, greatly reduced the inflammatory cytokine load and ameliorated bystander cell inflammatory responses more significantly than a broad-spectrum anti-inflammatory compound (BAY 11–7082). Our data suggest that the inflammatory mediators, especially IL-1β, may prime naïve cells to infection and lead to increased infection rates in microglial and astrocytoma cells. Cumulatively, our data suggest that the interplay between mitochondrial dysfunction and inflammatory events elicited in a neuronal microenvironment during a TC-83 infection may contribute to the spread of infection.

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Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways

Cited by 425 publications

References 26 publications

Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice

Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice

Nox4 has a crucial role in uric acid-induced oxidative stress and apoptosis in renal tubular cells

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

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