Role of IRAK-1 in the Dynamic Regulation of Reactive Oxygen Species
Generation of reactive oxygen species (ROS) by mammalian host cells is a double-edged sword. ROS are clearly beneficial in directly killing pathogens and as a signaling molecule to alert macrophages and neutrophils to the site of infection. However, ROS are also capable of damaging host cells by destroying DNA, oxidizing proteins and lipids, inactivating enzymes, and eliciting apoptosis. Therefore the balance of ROS generation and clearance is essential for homeostasis. Although multiple mechanisms can contribute to the generation of ROS, NADPH oxidase (Nox) is a primary producer. In terms of clearance, several ROS scavenging enzymes are induced by Nrf2, a sensor of excessive ROS. The mechanisms behind the skewing of this balance toward prolonged accumulation of ROS under chronic inflammatory conditions are not well understood.
Lipopolysaccharide (LPS), a major component of the Gram-negative bacteria cell wall, is specifically recognized by Toll-like receptor 4 (TLR4). LPS triggers robust activation of Nox and ROS production through TLR4, while also activating Nrf2 and ROS clearance. Intracellular pathways regulating ROS generation and clearance mediated by TLR4 are not well defined. Since interleukin-1 receptor associated kinase 1 (IRAK-1) is a key downstream component of TLR4, we test the hypothesis that IRAK-1 may play a critical role in maintaining the balance of LPS triggered ROS generation and clearance.
Using wild type and IRAK-1 deficient murine embryonic fibroblasts, we tested the dynamic induction of Nox1 (a key NADPH oxidase) and Nrf2 by varying dosages of LPS. Our data confirm that high dose LPS (as seen in acute bacterial infection) induced both Nox1 and Nrf2. The generation of Nox1 is IRAK-1 dependent. Low dose LPS (as seen in chronic metabolic endotoxemia) fails to induce Nrf2 and induces mild and prolonged expression of Nox1. Cells pre-challenged with low dose LPS are primed for more robust expression of ROS following a second LPS challenge. The conclusions and implications generated by this study are that chronic low dose endotoxemia (prevalent in adverse health conditions) may skew the balance of ROS generation and clearance to favor prolonged ROS accumulation, and that IRAK-1 represents a potential therapeutic target to treat chronic inflammatory diseases.