Mitochondria-derived reactive oxygen species negatively regulates immune innate signaling pathways triggered by a DNA virus, but not by an RNA virus

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Abstract

Reactive oxygen species (ROS) are crucial secondary messengers of signaling pathways. Redox-dependent signaling events have been previously described in the innate immune response. However, the mechanism by which ROS modulates anti-viral innate immune signaling is not fully clarified. Here, we report that mitochondria-derived ROS differentially regulate the innate response to DNA and RNA viruses (herpes simplex virus (HSV) and Sendai virus (SeV), respectively), with the cytokine response to HSV being negatively regulated by mitochondrial ROS. Importantly, specific activation of Toll-like receptors (TLRs) and DNA receptors (DNARs) but not retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), led to signaling cascades that were inhibited by mitochondrial ROS production. Thus, localized mitochondrial ROS exerts negative modulation of innate immune responses to the DNA virus HSV-2 but not the RNA virus SeV.

Highlights

► Determination of the role of ROS in innate immune signaling after viral infection. ► DNA and RNA viruses activate redox-dependent signaling pathways. ► Mitochondrial ROS regulate innate immune responses against DNA but not RNA viruses. ► Signaling activated by DNA-specific PRRs is regulated by mitochondrial ROS.

Introduction

The innate immune response relies on pattern recognition receptors (PRRs) for the detection of infectious agents [1]. TLRs are membrane-bound PRRs located in the plasma membrane and in endosomal compartments. Other PRRs, such as DNARs and RLRs are localized intra-cellularly. RLRs recognize 5′triphosphorylated RNA and dsRNA, whilst DNARs, such as IFI16 and DDX41, recognize DNA [2], [3], [4]. Activation of PRRs by a microbial infection induces intracellular signaling pathways which lead to the expression of cytokines and chemokines and the induction of an effective innate immune response against the invading pathogen.

Recent research demonstrates that ROS play an important role in the regulation of the virally-stimulated signaling pathways [5], [6], [7], [8]. ROS can be generated in different cellular compartments creating a local oxidant gradient that can oxidize nearby proteins [9]. Oxidation modifies protein function by disrupting complexes and inducing protein post-translational changes, thereby regulating immune signaling cascades [5], [10], [11].

In the present study, we determine the role of ROS in the signaling pathways engaged by a DNA and an RNA virus, HSV-2 and SeV, respectively. By using several inhibitors of proteins involved in ROS formation, we demonstrate that both viruses trigger redox-sensitive production of CCL5. However, mitochondrial-derived ROS specifically plays an essential role in negative regulation of the innate immune signaling triggered by DNA viruses.

Section snippets

Mice

C57BL/6 were bred at M&B Taconic (Laven, Denmark) and kept in the animal facility at The Faculty of Health Sciences, AU between the time of delivery (at 4–6 weeks of age) and the time of the experiments, and used for experiments between the age of 7 and 9 weeks old.

Cells—Peritoneal cells, pDCs, BMMs, BM-DCs, and RAW264.7 were obtained and cultured as previously described [5].

Reagents

Recombinant cytokines used for ELISAs were purchased from R&D Systems. The PRR agonists Poly(I:C), Pam3Csk4, and ODN1826

ROS-dependent cytokine induction by DNA and RNA viruses

ROS has gained increasing recognition as a second messenger in the activation of signaling pathways. Several reports have demonstrated that ROS play an important role in the regulation of innate immune signaling [5], [6], [7], [10], [15], [16]. However, the mechanisms and the components that ROS regulate are still poorly understood. To determine the role of redox-dependent regulation of innate immune signaling triggered by DNA or RNA viruses, murine peritoneal macrophages or cells from the

Discussion

ROS have been shown to play a role regulating innate immune responses through the modulation of the signal transduction cascades [5], [6], [7], [8]. However, the mechanisms by which ROS modifies these pathways are not completely understood. Nevertheless, ROS distribution may be one of the factors that contribute to differential regulation of signaling cascades. Woo et al. have shown that transient and localized production of ROS creates an oxidative gradient that regulates the activity of

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