Molecular mechanism underlying LPS‐induced generation of reactive oxygen species in macrophages

The generation of reactive oxygen species (ROS) by host macrophages plays a critical role during the pathogenesis of diverse inflammatory diseases. Bacterial lipopolysaccharide (LPS) triggers the expression of ROS through multiple mechanisms including the activation and induction of NADPH oxidase, as well as the suppression of anti‐oxidative enzymes involved in ROS clearance. However, the underlying molecular mechanisms are poorly defined. The objective of this study is to systematically define the molecular mechanisms underlying the induction of ROS by LPS in macrophages. Using bone marrow derived macrophages (BMDM) harvested from wild type (WT) or IRAK‐1 (interleukin‐1 receptor associated kinase 1) deficient mice, we observed that LPS induced significantly less ROS in IRAK‐1 −/− macrophages, indicating that IRAK‐1 is critically involved in the induction of ROS. Mechanistically, we observed that IRAK‐1 is required for LPS‐induced expression of NOX‐1, a key component of NADPH oxidase, via multiple transcription factors including p65/RelA, C/EBPβ and C/EBPδ. On the other hand, we demonstrated that IRAK‐1 associated with and activated small GTPase Rac1, a known activator of NOX‐1 oxidase enzymatic activity. IRAK‐1 forms a close complex with Rac1 via a poly‐proline motif within the variable region of IRAK‐1. On the other hand, we also observed that IRAK‐1 is required for LPS‐mediated suppression of PPARα and PGC‐1α, nuclear factors essential for the expression of anti‐oxidative enzymes such as GPX3 and catalase. Consequently, injection of LPS causes significantly less plasma lipid peroxidation in IRAK‐1 −/− mice compared to wild type mice. Taken together, our study reveals IRAK‐1 as a novel component involved in the generation of ROS induced by LPS. This study is supported by a grant from NIH (R01 AI64414).