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

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.

Mechanisms of concanavalin A-induced cytokine synthesis by hepatic stellate cells: Distinct roles of interferon regulatory factor-1 in liver injury

“…Our findings suggest that ConA/HSC-induced inhibition of SOD1 in hepatocytes may be an important reason for increased oxidative stress. Whether increased nuclear IRF1 in ConA/HSC-challenged hepatocytes regulates SOD1, remains to be determined, but LPS-induced IRF1 has been implicated in SOD consumption and increased mitochondrial damage in macrophages (43). Consistent with the role of activated JNK in repressing SOD1 gene transcription/activity (24, 25), we found improved SOD activity in hepatocytes pretreated with JNK inhibitor or anti-IFN␤ Ab.…”

Modulating T Cell Responses via Autophagy: The Intrinsic Influence Controlling the Function of Both Antigen-Presenting Cells and T Cells

“…IL-10 may simultaneously regulate autophagy/ mitophagy through activation of AMPK (135, 159). Another study has shown that LPS induces the expression of interferon regulatory factor-1 (IRF-1), which increases mitochondrial damage (160) and inhibits macrophage mitophagy (161, 162). It is not fully clear whether IRF-1 directly regulates IL-10, or vice versa, but one study has demonstrated that Irf1 −/− DC express higher levels of IL-10 (163), suggesting a possible connection.…”

Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy‑mediated NLRP3 inflammasome inactivation in sepsis

“…Macrophages are the first line of defense against pathogens in sepsis (25). Macrophage mitochondrial dysfunction is involved in the pathogenesis of sepsis through several mechanisms, including systemic inflammatory responses, oxidative stress, energy metabolism and the intrinsic apoptotic pathway (26). It was previously reported that mitochondrial dysfunction induced by LPS is associated with mtDNA depletion and results in a lack of mitochondrial transcription (27,28).…”