Metabolic sensor Gpr35 links dietary lipids to itch mediating neural circuits

Impact of nutrition on systemic health is well-recognized but the specific sensors that couple western dietary lipid metabolites into the pathological triggers of chronic itch and inflammation remain elusive. Here, we identify a metabolic- to-sensory axis in which 9-keto-12,13-epoxy octadecenoic acid (EKODE), an endogenous dietary linoleic acid derivative acts as a potent ligand for the G protein-coupled receptor 35 (Gpr35) to drive chronic itch, inflammation, and heat hypersensitivity. We demonstrate that Gpr35 is selectively expresses in a distinct population of sensory neurons and genetic ablation of Gpr35 in sensory neurons attenuates EKODE and psoriasis-associated itch and inflammation. Furthermore, pharmacological inhibition of Gpr35 significantly attenuates itch in mouse models of psoriasis and atopic dermatitis. We show that Gpr35 signaling engages the itch-specific brain natriuretic peptide, defining a labeled-line pathway that is functionally distinct from classical nociceptive circuits. Collectively, our findings establish Gpr35 as a critical neuro-metabolic sensor in healthy and disease conditions.