Scientists have identified a receptor on sensory nerves that appears to detect a fatty-acid byproduct found at high concentrations in psoriatic skin. In mice, blocking or deleting the receptor reduced itching and skin thickening, suggesting that it could become a treatment target for psoriasis and eczema-like inflammation.
“Linoleic acid is a naturally occurring fatty acid found in foods ranging from nuts and seeds to vegetable oils,” said lead author Professor Santosh Mishra, a researcher at North Carolina State University’s College of Veterinary Medicine.
“Humans need to consume small amounts of linoleic acid, but excessive intake is associated with chronic heart disease and diabetes, among others.”
“We also know that certain polyunsaturated fat-derived molecules are associated with itch, and that linoleic acid is the most abundant polyunsaturated fat in both the skin and the Western diet.”
“We wanted to investigate the relationship between linoleic acid and itch.”
Tracing the itch pathway
Professor Mishra and his colleagues had previously found that a linoleic acid derivative called EKODE, or 9-keto-12,13-epoxyoctadecenoic acid, occurs at higher concentrations in psoriasis lesions than in unaffected skin. Injecting EKODE into mice caused them to scratch, but it was unclear how the body detected the molecule.
The new study points to Gpr35, a receptor found on a subset of sensory neurons involved in transmitting itch signals.
In cultured mouse neurons, EKODE triggered calcium signals—a marker of neuronal activation—in about 9% of the cells. Blocking Gpr35 with a chemical compound or deleting the gene reduced these responses.
Mice engineered to lack Gpr35 in sensory neurons that detect pain and itch scratched much less after EKODE injections. However, they responded normally to histamine, a classic itch trigger, indicating that the receptor is not required for every form of itch.
Effects in a psoriasis model
The researchers then used a standard mouse model of psoriasis, in which the drug imiquimod is applied to the skin.
Mice lacking the receptor developed less skin thickening and scratched less than normal mice. A single injection of a Gpr35-inhibiting compound also reduced scratching in normal mice with psoriasis-like or eczema-like skin.
The scientists further found that the neuropeptide Nppb, which has previously been implicated in itch, appears to act downstream of the receptor. Mice lacking Nppb scratched less and developed thinner skin in the psoriasis model.
Mice lacking Gpr35 also took longer to move away from some hot surfaces, although they showed no differences in tests involving cold or touch.
Relevance to human disease
According to the authors, GPR35 is present in human sensory neurons. In samples from two donors, every Nppb-expressing neuron examined also expressed GPR35.
“This study shows the importance of GPR35, as this receptor is involved in two very different diseases: autoimmune and allergic diseases,” Professor Mishra said.
“However, in both diseases, the itch pathway uses the same receptors. This means that GPR35 is a promising therapeutic target for both diseases.”
The findings appear in the journal Communications Biology.
JJ Wheeler et al. 2026. Metabolic sensor Gpr35 links dietary lipids to itch-mediating neural circuits. Communications Biology 9, 1393. doi:10.1038/s42003-026-11087-x
Source: www.sci.news
