THE G-PROTEIN COUPLED RECEPTOR OXER1 IS A TISSUE REDOX SENSOR ESSENTIAL FOR INTESTINAL EPITHELIAL BARRIER INTEGRITY

Abstract Controlled production of reactive oxygen species at barrier tissues is an important part of the innate immune response but also damages the host tissue. Generating microbicidal levels of reactive oxygen species (ROS) requires adaptation of mucosal barriers. High tolerance of ROS provides improved innate immune defenses against pathogens, whereas low tolerance renders host cells prone to chronic toxicity and mutagenesis, which leads to tissue damage, inflammation and cancerogenesis. Inappropriate (either insufficient or excessive) ROS production has been implicated in the pathogenesis of inflammatory bowel disease (IBD), however the mechanisms that sense and mediate tolerance to ROS in the intestine are little understood. The arachidonic acid derivative 5-oxo-eicosatetraenoic acid (5-oxo-ETE) is known to attract leukocytes to damaged or infected mucosal barriers by signaling through its receptor, OXER1 (oxoeicosanoid receptor 1). Intriguingly, previous human data has reported that 5-oxo-ETE levels are elevated in mucosa of healthy tissue compared to the neighboring inflamed tissue in IBD patients. However, little is known about the role of 5-oxo-ETE in IBD because its receptor is absent from rodents, the most common model organism used in IBD research. We have found an unexpected, non-immune role for 5-oxo-ETE in redox adaptation of the intestinal mucosa. Genetic deletion of the zebrafish OXER1 ortholog hcar1-4 causes barrier defects and baseline inflammation in the intestine of live zebrafish larvae. Mechanistically, OXER1 signaling protects against oxidative nucleotide lesions by inducing the expression of DNA-protective Nudix hydrolase enzymes in the zebrafish intestinal epithelium and also in cultured human intestinal epithelial cells. In conclusion, we show that the OXER1 pathway acts as a conserved ROS resilience mechanism that fortifies pathogen-exposed mucosal linings against increased oxidative stress in vivo. In the future, modulation of this pathway may lead to new therapies to boost epithelial resilience and mucosal regeneration in IBD patients.