Fatty Acid Byproduct in Skin Triggers Chronic Itch via Nerve Receptor
Scientists have identified that EKODE, a linoleic acid derivative found in high levels in psoriasis skin, activates the Gpr35 receptor on sensory nerves to drive chronic itch and inflammation. Blocking this receptor reduced scratching and skin thickening in mouse models of psoriasis. The findings reveal a metabolic-to-sensory pathway linking dietary fats to neurological symptoms, offering new targets for treating inflammatory skin conditions.
Scientists at North Carolina State University’s College of Veterinary Medicine, led by Professor Santosh Mishra, have uncovered a direct link between a fatty acid byproduct called EKODE and chronic itch in psoriasis through the Gpr35 receptor on sensory nerves. EKODE, a derivative of linoleic acid—abundant in nuts, seeds, and vegetable oils—is found at elevated levels in psoriatic skin lesions. In mouse models, injecting EKODE induced scratching behavior, which was significantly reduced when Gpr35 was blocked or genetically deleted. Mice lacking Gpr35 in itch-sensing neurons scratched less after EKODE injection and showed reduced skin thickening in a psoriasis-like model induced by imiquimod. The study also revealed that the neuropeptide Nppb, previously associated with itch signaling, acts downstream of Gpr35, as mice lacking Nppb exhibited less scratching and thinner skin. Calcium signaling experiments confirmed EKODE activated sensory neurons in about 9% of cultured mouse neurons, an effect diminished when Gpr35 was inhibited. The receptor GPR35 is also present in human sensory neurons, with co-expression observed in all Nppb-expressing neurons from two donors. This suggests a conserved pathway across species. While linoleic acid is essential in small amounts, overconsumption has been linked to metabolic diseases, adding context to how dietary fats may influence neurological symptoms via metabolic byproducts.
The research builds on prior findings that polyunsaturated fat
This discovery could reshape treatment strategies for chronic inflammatory skin conditions like psoriasis and eczema, where persistent itch significantly impacts quality of life. If Gpr35 inhibitors prove effective in humans, they may offer a new class of targeted therapies that reduce both itching and skin thickening without suppressing the immune system broadly. Pharmaceutical companies developing anti-itch or anti-inflammatory drugs may prioritize GPR35 as a novel target, potentially influencing drug development pipelines. The finding also underscores the role of diet—particularly polyunsaturated fats—in neurological symptoms, which could prompt public health messaging about dietary moderation in at-risk populations. A comparable precedent is the success of biologics targeting IL-17 or TNF-alpha in psoriasis, which transformed treatment but required expensive, injectable formulations. GPR35 blockers, if developed as oral drugs, might offer a more accessible alternative. However, it