Role of interferon regulatory factor-1 in lipopolysaccharide-induced mitochondrial damage and oxidative stress responses in macrophages

Deng,Song-Yun; Zhang,Le-Meng; Ai,Yu-Hang; Pan,Pin-Hua; Zhao,Shuang-Ping; Su,Xiao-Li; Wu,Dong-Dong; Tan,Hong-Yi; Zhang,Li-Na; Tsung,Allan

doi:10.3892/ijmm.2017.3110

Role of interferon regulatory factor-1 in lipopolysaccharide-induced mitochondrial damage and oxidative stress responses in macrophages

Authors:
- Song-Yun Deng
- Le-Meng Zhang
- Yu-Hang Ai
- Pin-Hua Pan
- Shuang-Ping Zhao
- Xiao-Li Su
- Dong-Dong Wu
- Hong-Yi Tan
- Li-Na Zhang
- Allan Tsung
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Affiliations: Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Published online on: August 25, 2017 https://doi.org/10.3892/ijmm.2017.3110
Pages: 1261-1269
Copyright: © Deng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sepsis causes many early deaths; both macrophage mitochondrial damage and oxidative stress responses are key factors in its pathogenesis. Although the exact mechanisms responsible for sepsis-induced mitochondrial damage are unknown, the nuclear transcription factor, interferon regulatory factor-1 (IRF-1) has been reported to cause mitochondrial damage in several diseases. Previously, we reported that in addition to promoting systemic inflammation, IRF-1 promoted the apoptosis of and inhibited autophagy in macrophages. In the present study, we hypothesized that lipopolysaccharide (LPS)-induced IRF-1 activation in macrophages may promote mitochondrial damage and oxidative stress. In vitro, LPS was found to promote IRF-1 activation, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) depletion, superoxide dismutase (SOD) consumption, malondialdehyde (MDA) accumulation and mitochondrial depolarization in macrophages in a time- and dose-dependent manner. These effects were abrogated in cells in which IRF-1 was knocked down. Furthermore, IRF-1 overexpression increased LPS-induced oxidative stress responses and mitochondrial damage. In vivo, peritoneal macrophages obtained from IRF-1 knockout (KO) mice produced less ROS and had less mitochondrial depolarization and damage following the administration of LPS, when compared to their wild-type (WT) counterparts. In addition, IRF-1 KO mice exhibited a decreased release of mitochondrial DNA (mtDNA) following the administration of LPS. Thus, IRF-1 may be a critical factor in augmenting LPS-induced oxidative stress and mitochondrial damage in macrophages.

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