Oxoeicosanoid signaling mediates early antimicrobial defense in zebrafish

5-oxoETE is a bioactive lipid derived from arachidonic acid generated when phospholipase A(2) activation coincides with oxidative stress. Through its G protein-coupled receptor OXER1, pure 5-oxoETE is a potent leukocyte chemoattractant. Yet, its physiological function has remained elusive owing to the unusual OXER1 conservation pattern. OXER1 is conserved from fish to primates but not in rodents, precluding genetic loss-of-function studies in mouse. To determine its physiological role, we combine transcriptomic, lipidomic, and intravital imaging assays with genetic perturbations of the OXER1 ortholog hcar1–4 in zebrafish. Pseudomonas aeruginosa infection induces the synthesis of 5-oxoETE and its receptor, along with other inflammatory pathways. Hcar1–4 deletion attenuates neutrophil recruitment and decreases post-infection survival, which could be rescued by ectopic expression of hcar1–4 or human OXER1. By revealing 5-oxoETE as dominant lipid regulator of the early antimicrobial response in a non-rodent vertebrate, our work expands the current, rodent-centric view of early inflammation.