Metabolic sensor Gpr35 links dietary lipids to itch mediating neural circuits

Abstract

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.

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BibTeX

@article{wheeler2026metabolic,
  title = {{Metabolic sensor Gpr35 links dietary lipids to itch mediating neural circuits}},
  author = {Joshua J. Wheeler and Alla Lyfenko and Nesia A. Zurek and Keaton Song and Andy Wangzhou and Sruti Bontala and Ojasvi Deep and Jacob Casey and Ramsey Kubofcik and Daniel L. Schaffer and Hassan Melhem and Gregory S. Keyes and John M. Davis and Jan Hendrik Niess and Theodore J. Price and Christopher E. Ramsden and Brian S. Kim and Sascha R. A. Alles and Santosh K. Mishra},
  journal = {Communications Biology},
  year = {2026},
  month = oct,
  doi = {10.1038/s42003-026-11087-x},
  url = {https://www.nature.com/articles/s42003-026-11087-x},
  note = {CC BY-NC-ND 4.0},
}

RIS

TY  - JOUR
TI  - Metabolic sensor Gpr35 links dietary lipids to itch mediating neural circuits
AU  - Joshua J. Wheeler
AU  - Alla Lyfenko
AU  - Nesia A. Zurek
AU  - Keaton Song
AU  - Andy Wangzhou
AU  - Sruti Bontala
AU  - Ojasvi Deep
AU  - Jacob Casey
AU  - Ramsey Kubofcik
AU  - Daniel L. Schaffer
AU  - Hassan Melhem
AU  - Gregory S. Keyes
AU  - John M. Davis
AU  - Jan Hendrik Niess
AU  - Theodore J. Price
AU  - Christopher E. Ramsden
AU  - Brian S. Kim
AU  - Sascha R. A. Alles
AU  - Santosh K. Mishra
PY  - 2026
DA  - 2026/10/29
JO  - Communications Biology
DO  - 10.1038/s42003-026-11087-x
UR  - https://www.nature.com/articles/s42003-026-11087-x
AB  - 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.
SN  - 2399-3642
ER  -

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