Inside-Out Signaling Pathways from Nuclear Reactive Oxygen Species Control Pulmonary Innate Immunity

Abstract

The airway mucosa is responsible for mounting a robust innate immune response (IIR) upon encountering pathogen-associated molecular patterns. The IIR produces protective gene networks that stimulate neighboring epithelia and components of the immune system to trigger adaptive immunity. Little is currently known about how cellular reactive oxygen species (ROS) signaling is produced and cooperates in the IIR. We discuss recent discoveries about 2 nuclear ROS signaling pathways controlling innate immunity. Nuclear ROS oxidize guanine bases to produce mutagenic 8-oxoguanine, a lesion excised by 8-oxoguanine DNA glycosylase1/AP-lyase (OGG1). OGG1 forms a complex with the excised base, inducing its nuclear export. The cytoplasmic OGG1:8-oxoG complex functions as a guanine nucleotide exchange factor, triggering small GTPase signaling and activating phosphorylation of the nuclear factor (NF)κB/RelA transcription factor to induce immediate early gene expression. In parallel, nuclear ROS are detected by ataxia telangiectasia mutated (ATM), a PI3 kinase activated by ROS, triggering its nuclear export. ATM forms a scaffold with ribosomal S6 kinases, inducing RelA phosphorylation and resulting in transcription-coupled synthesis of type I and type III interferons and CC and CXC chemokines. We propose that ATM and OGG1 are endogenous nuclear ROS sensors that transmit nuclear signals that coordinate with outside-in pattern recognition receptor signaling, regulating the IIR.

BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

“…These pathways coordinate expression of highly inducible immediate early genes encoding secreted factors whose actions stimulate neighboring epithelia and components of the immune system to trigger dendritic cell activation and the downstream adaptive immune response (18,19). In response to nuclear ROS signals, coupled posttranslational modifications of RelA enable complex formation with P-TEFb, an event necessary for rapid transcriptional activation of immediate early genes (19,21,37). In this study, we investigate the requirement for and mechanism of BRD4 in controlling innate signaling downstream of the RIG-I and TLR3 PRRs.…”

“…In addition, we previously observed that RSV-activated RelA binds to the IRF7 promoter and is required for IRF7 expression (11); that both RelA and IRF7 bind to the RIG-I promoter, potentiating RIG-I expression (10); and that RIG-I is required for sustained type I IFN expression using siRNA-mediated silencing (30). With IFN=s secondary effect on IRF1/7 upregulation, a positive regulatory loop is established, producing an antiviral response (10,11,37). The functional role of NF-B in IRF1-RIG-I amplification has not been systematically examined.…”

Mitochondrial DNA Damage Initiates Acute Lung Injury and Multi-Organ System Failure Evoked in Rats by Intra-Tracheal Pseudomonas Aeruginosa

“…This finding points to the prospect that mtDNA damage and repair could exert more complex actions governing the response to bacterial injury than initially anticipated. In this regard, Boldogh and colleagues demonstrated that free 8-oxoguanine, which is excised from oxidatively damaged DNA by Ogg1, forms a complex with the glycosylase to function as a guanine exchange factor activating Ras -dependent signaling, particularly those pathways driving innate immune responses (28). Importantly, 8-oxoguanine binds to Ogg1 at a site distinct from its DNA binding and repair domain of the protein.…”

Systematic Analysis of Cell-Type Differences in the Epithelial Secretome Reveals Insights into the Pathogenesis of Respiratory Syncytial Virus–Induced Lower Respiratory Tract Infections

“…Enhanced activation of innate inflammation has been demonstrated in children with bronchiolitis, where enhanced expression of IL-6, -8 and MIP-1β have been observed (16). Important to the pathogenesis of LRTI, the epithelium in the proximal conductive airways and the respiratory surface play functionally distinct roles in innate defenses (17, 18). Under normal conditions, inhaled pathogens are cleared via the mucociliary escalator from ciliated epithelial cells.…”