Linoleic Acid Derivative Linked to Chronic Psoriasis Itch via Gpr35 Receptor
Scientists identify a metabolic-to-sensory pathway where dietary fat byproducts trigger chronic skin inflammation.
1Metabolic-to-Sensory Axis Discovery
Researchers identified a specific metabolic-to-sensory axis where EKODE, a byproduct of dietary linoleic acid, drives chronic itch. This fatty acid derivative acts as a potent ligand for the G protein-coupled receptor 35, known as Gpr35. This discovery provides a molecular explanation for why psoriasis lesions exhibit heightened sensitivity and persistent inflammation.
2Linoleic Acid and Skin Health
Linoleic acid is a common polyunsaturated fat found in vegetable oils, nuts, and seeds. While essential in small amounts, excessive consumption correlates with chronic conditions like heart disease and diabetes. The study highlights that this abundant dietary fat is also highly concentrated in skin, potentially fueling localized inflammatory responses.
3Gpr35 Receptor Functionality
The Gpr35 receptor is located on sensory neurons responsible for transmitting itch signals to the brain. In cultured mouse neurons, EKODE triggered calcium signaling in approximately 9% of cells, marking nerve activation. Genetic deletion or chemical blocking of this receptor significantly reduced these cellular responses, proving its role in signal transmission.
4Mouse Model Experimental Results
Mice engineered to lack Gpr35 showed reduced scratching and thinner skin in imiquimod-induced psoriasis models. These subjects responded normally to histamine, indicating that Gpr35 operates through a distinct pathway from classic itch triggers. This specificity suggests that targeting Gpr35 could mitigate symptoms without disrupting other essential sensory functions in the body.
5Downstream Neuropeptide Nppb Involvement
The study identified the neuropeptide Nppb as a downstream mediator of the Gpr35 pathway. Mice lacking Nppb exhibited thinner skin and reduced scratching behavior in psoriasis models. This confirms that Nppb acts after the Gpr35 receptor activation, effectively bridging the gap between metabolic lipid detection and the physical sensation of itch.
6Human Sensory Neuron Expression
Analysis of human donor samples confirmed that GPR35 is present in sensory neurons. Every neuron expressing Nppb also expressed GPR35, suggesting the mechanism is conserved across species. This alignment between mouse models and human tissue samples strengthens the potential for developing clinical therapies that target this specific receptor in human patients.
7Therapeutic Potential Across Diseases
Professor Santosh Mishra notes that GPR35 is connected to both autoimmune and allergic diseases. Because the itch pathway utilizes this same receptor in both conditions, GPR35 emerges as a promising therapeutic target. Developing drugs to block this receptor could provide relief for patients suffering from chronic, treatment-resistant skin conditions globally.
8Future Research and Implications
Published in Communications Biology, this research establishes a clear link between dietary lipids and neural circuits. While the study focused on psoriasis, the dual role of GPR35 in allergic and autoimmune pathways warrants further investigation. Future clinical trials will need to evaluate the efficacy of GPR35-blocking compounds in human dermatological treatments.