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. Using cell physiology, bioinformatics, pharmacology, mouse genetics and behaviour, we uncover metabolic-neuronal pathways for itch. We show that the linoleic acid metabolite EKODE acts via Gpr35 to trigger inflammation and itch in skin conditions.

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Journal
Communications Biology
Published
2026-10-29
DOI
https://doi.org/10.1038/s42003-026-11087-x
Primary Topic
Dermatology and Skin Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

Metabolic sensor Gpr35 links dietary lipids to itch mediating neural circuits

Santosh Kumar Mishra, Andi Wangzhou, Nesia A. Zurek, Gregory S. Keyes et al.
1 links
Communications Biology
Dermatology and Skin Diseases
article

Metabolic sensor Gpr35 links dietary lipids to itch mediating neural circuits

Santosh Kumar Mishra, Andi Wangzhou, Nesia A. Zurek, Gregory S. Keyes, Jan Hendrik Niess, Theodore John Price, Sascha R.A. Alles, John M. Davis, Joshua J. Wheeler, Christopher E. Ramsden, Ojasvi Deep, Brian Kim, Hassan Melhem, Ramsey Kubofcik, Jacob Casey, Sruti Bontala, Alla Lyfenko, Daniel L. Schaffer
article en

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. Using cell physiology, bioinformatics, pharmacology, mouse genetics and behaviour, we uncover metabolic-neuronal pathways for itch. We show that the linoleic acid metabolite EKODE acts via Gpr35 to trigger inflammation and itch in skin conditions.

Communications BiologyVol. 9(1)
Cincinnati Children's Hospital Medical Center (US), National Institutes of Health (US), Northwell Health (US), Feinstein Institute for Medical Research (US), North Carolina State University (US), The University of Texas at Dallas (US), University of Basel (CH), University of Illinois Chicago (US), National Institute on Alcohol Abuse and Alcoholism (US), National Institute on Aging (US), Icahn School of Medicine at Mount Sinai (US)
Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Sanofi, North Carolina State University, Regeneron Pharmaceuticals, Galderma, LEO Pharma, National Institutes of Health, Genentech, National Institute of Arthritis and Musculoskeletal and Skin Diseases, H2020 European Research Council
Good health and well-being
Openalex Percentile: Top 10%
Dermatology and Skin Diseases
DOIOpen Access PDFOpenAlex
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