The G-protein coupled receptor OXER1 is a tissue redox sensor essential for intestinal epithelial barrier integrity.

Generation of reactive oxygen species is an important part of the innate immune response. 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 can promote inflammation (e.g., in asthma and Crohn's disease) and cancerogenesis. The mechanisms that sense and mediate host tolerance to ROS are little understood. In this study, we discover an unexpected role for the redox-sensitive, chemokine-like lipid 5-oxo-eicosatetraenoic acid (5-KETE) in redox adaptation. 5-KETE is known to attract leukocytes to damaged/infected mucosal barriers by signaling through its receptor, OXER1. Suggestive of a distinct non-immune function, we here report that the loss of the OXER1 ortholog Hcar1-4 causes barrier defects and baseline inflammation in the intestine of live zebrafish larvae. In zebrafish and cultured human cells, OXER1 signaling protects against oxidative nucleotide lesions by inducing DNA-protective Nudix hydrolases. Our data reveal the oxoeicosanoid pathway as a conserved ROS resilience mechanism that fortifies pathogen-exposed mucosal linings against increased oxidative stress