Do you suffer from psoriasis? Blame it on this trio of proteins

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About 7.5 million Americans have psoriasis, an autoimmune disease that manifests as patches of red, inflamed skin and painful, scaly rashes. While there are effective treatments for psoriasis, not everyone responds to these therapies and for many, relief is temporary.

“These therapies do not reduce disease 100 percent, and they do not cure disease,” says Professor Michael Croft, Ph.D. of the La Jolla Institute of Immunology (LJI). “And if you take the patients off these drugs, the disease almost always comes back. “

Croft and his team at the LJI’s Center for Autoimmunity and Inflammation have discovered how a key protein called TWEAK damages skin cells in patients with psoriasis. Their findings, in mice and with human skin cells, suggest that targeting TWEAK may help control the disease

“We believe that TWEAK could be considered a potential target for the treatment of psoriasis,” says Rinkesh Gupta, Ph.D., postdoctoral fellow at LJI and first author of the new Science Immunology study. “It’s good to have this chance to develop a new therapeutic option.”

The results build on previous work from the Croft Lab showing that TWEAK can interact with the most common type of skin cell called a keratinocyte. By studying TWEAK-deficient mice, researchers found that TWEAK drives inflammation in a model of psoriasis.

The new study shows that TWEAK does not work on its own. By studying human keratinocytes, researchers found that TWEAK combines with two other proteins, called tumor necrosis factor (TNF) and interleukin-17 (IL-17), to trigger inflammation. This trio appears to control the production of inflammatory molecules and the expression of additional proteins associated with inflammation in patients with psoriasis.

“The fact that they work together suggests that the disease is primarily caused by these three particular proteins at the same time,” says Croft. “The main implication is that TWEAK will also be a good drug target. as has already been proven for TNF and IL-17.

To test this, the researchers used a mouse model of psoriasis to compare how well a TWEAK inhibitor was measured versus therapies that inhibit IL-17 or TNF.

The results suggest the team is on the right track. “If you prevent TWEAK from working on its receptor on keratinocytes, you get the same therapeutic effect as when you inhibit TNF or IL-17,” Gupta explains. This finding is particularly encouraging because TNF and IL-17 are both FDA approved drug targets for psoriasis.

Although human clinical trials are yet to be done, Croft sees a future for TWEAK inhibitors as therapies for many types of skin diseases. “We believe that TWEAK is involved in inflammation of the skin in general,” explains Croft.

His lab is currently studying the role of TWEAK in atopic dermatitis, also known as eczema, a very common type of skin inflammation, especially in babies and young children. Croft says that while psoriasis and atopic dermatitis are separate illnesses, they have a few things in common and there aren’t as many good treatments for atopic dermatitis.

“There is certainly a lot of room for improving the treatment of patients with atopic dermatitis,” he says.

The study, “TWEAK works with TNF and IL-17 on keratinocytes and is a potential target for the treatment of psoriasis,” was supported by the National Institutes of Health (grant AR072640).

Additional study authors include Donald T. Gracias, Daniela Salgado Figueroa, Haruka Miki, Jacqueline Miller, Kai Fung, Ferhat Ay, and Linda Burkly.

DOI: 10.1126 / sciimmunol.abi8823

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