A team of researchers has found that a breakdown product from a commonly consumed fat can bind to a receptor associated with psoriatic itch and inflammation. By blocking the receptor, the researchers saw a reduction in psoriatic itch in a mouse model. The work demonstrates the potential impact of diet on chronic itch triggers and could lead to future therapies for both psoriasis and atopic dermatitis.
Linoleic acid is a naturally occurring fatty acid that is found in foods ranging from nuts and seeds to vegetable oils. While humans need to consume linoleic acid in small amounts, overconsumption has been associated with chronic heart disease and diabetes, among other conditions.
"We also know that certain polyunsaturated fat-derived molecules are associated with itch, and that linoleic acid is the most abundant polyunsaturated fat found in both skin and western diets," says Santosh Mishra, professor of molecular and biomedical sciences in North Carolina State University's College of Veterinary Medicine. "We wanted to explore connections between linoleic acid and itch." Mishra is the corresponding author of the study describing the work.
Specifically, the researchers focused on a derivative of linoleic acid known as 9-keto-12,13-epoxy octadecenoic acid (EKODE), which has been found in high concentrations in psoriatic lesions and shown to induce itching behavior in mice.
In humans and rodents, primary sensory neurons within the dorsal root ganglia (DRG) express specific ion channels, including TRPV1 and TRPA1, which mediate pain, thermal sensation, and itch.
Using EKODE, mouse DRG and cultured human DRG neurons, the researchers found the signaling pathway that connected EKODE from periphery in the skin to the spinal cord via a neuropeptide called BNP, which is specifically associated with itch response.
In short, they found that EKODE binds to and activates a receptor called GPR35 on sensory neurons, which in turn release BNP and drive the itch response.
The researchers also confirmed GPR35 receptor expression on "TRPV1" and "TRPA1" sensory neurons in both rodent and human DRG neurons.
Next, the researchers looked at how the pathway works in a mouse model of psoriasis. They compared itch response to EKODE in mice with and without the GPR35 receptor and found that the GPR35 knockout mice had less inflammation and itch than those with GPR35.
They did the same thing with BNP knockout mice and saw similarly reduced itch and inflammation in the psoriasis model.
Finally, they treated a mouse model of eczema with a GPR35 blocker and found that the itch response was significantly reduced in that case as well.
The researchers hope that the work can lead to therapies for both psoriasis and other chronic itch conditions, like atopic dermatitis, in both human and veterinary fields.
"The work shows the importance of GPR35 because this receptor is connected to two totally different diseases - one autoimmune and one allergic," Mishra says. "But in both diseases the itch pathway is using the same receptor, which means that GPR35 is a promising therapeutic target for both diseases."
The work appears in Communications Biology. The National Institutes of Health provided approximately 50% of the support for the work. Joshua Wheeler, postdoctoral researcher at NC State, is the first author. Other NC State contributors include Alla Lyfenko, Sruti Bontala, Ojasvi Deep, and Jacob Casey. Nesia A. Zurek and Sascha R.A. Alles of Cincinnati Children's Hospital Medical Center; Keaton Song, Ramsey Kubofcik, Daniel L. Schaffer and Brian S. Kim of the Icahn School of Medicine at Mount Sinai; Andy Wangzhou and Theodore Price of the University of Texas at Dallas; Hassan Melhem and Jan Hendrik Niess of the University of Basel, Switzerland; Gregory S. Keyes and Christopher E. Ramsden of the National Institutes of Health; and John M. Davis of the University of Illinois at Chicago also contributed to the work.
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