Psoriasis on an elbow showing redness and dry patches.[QUAYSIDE/Getty Images]

Red, inflamed skin and painful scaly rashes are a hallmark of psoriasis, an autoimmune disease that affects nearly 125 million people worldwide. Available therapies impart limited, temporary or no relief to many patients suffering from the disease.

“These therapies don’t reduce disease by 100 percent, and they don’t cure the disease” says Michael Croft, PhD, professor at the Center for Autoimmunity and Inflammation at the La Jolla Institute for Immunology (LJI). “And if you take patients off those drugs, the disease almost always comes back.”

Croft and his team have discovered how a cytokine protein called TWEAK damages skin cells in psoriasis patients. Their findings in mice and in human skin cells, published in an article titled “TWEAK functions with TNF and IL-17 on keratinocytes and is a potential target for psoriasis therapy,” in the journal Science Immunology, suggest targeting TWEAK may offer an alternative therapeutic approach in treating the disease.

“We think TWEAK might be considered a potential target for the treatment of psoriasis,” says Rinkesh Gupta, PhD, a postdoctoral fellow at LJI and first author of the study. “It’s good to have this chance to develop a new therapeutic option.”

Earlier work has shown an increase of soluble TWEAK is in the serum of patients with psoriasis, and an increased expression of both TWEAK and its receptor, Fn14, in tissue sections from psoriatic lesions of the skin, suggesting that neutralizing the TWEAK/Fn14 pathway could potentially reduce skin pathology in psoriasis.

Earlier experiments in Croft’s Lab has shown TWEAK interacts with keratinocytes—a cell in the skin’s epidermis that produces keratin. Mice lacking TWEAK, the researchers had found, showed impaired expression of disease-linked chemokines and cytokines and reduced skin inflammation while subcutaneous injection of TWEAK into healthy mice provoked skin inflammation with the molecular and histological hallmarks of psoriasis.

In the current study, the researchers show TWEAK is part of an inflammatory trio. By studying human keratinocytes in culture, the researchers have discovered TWEAK teams up with two other cytokine proteins, tumor necrosis factor (TNF) and interleukin-17 (IL-17), to trigger inflammation. The trio appears to control the production of pro-inflammatory signals in patients with psoriasis.

Earlier work has shown targeting TNF and IL-17 is effective in treating patients with psoriasis, but whether these molecules act with other inflammatory factors was not known until now. Drugs targeting TNF and IL-17 are FDA-approved for psoriasis.

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

In the current study the researchers pharmacologically inhibit TWEAK and compare this approach to inhibiting IL-17 or TNF in a mouse model of psoriasis. “If you inhibit TWEAK from working on its receptor on keratinocytes, you get the same therapeutic effect as when you inhibit TNF or IL-17,” says Gupta.

“Blocking TWEAK could be comparable to targeting TNF or IL-17 and might be considered as an alternate therapeutic treatment for psoriasis,” the authors noted in the paper.

Mice having a keratinocyte-specific deletion of the receptor for TWEAK, Fn14, display reduced skin inflammation upon chemical induction, including decreased epidermal hyperplasia (an increase in the number of cells within the epidermal layers of the skin) and less expression of psoriasis signature genes, the authors reported.

They also conducted transcriptomic studies in human keratinocytes that uncovered TWEAK displayed strong synergism with inflammatory molecules in up-regulating mRNA for many psoriasis-associated genes in human keratinocytes.  This implies TWEAK enhances feedback inflammatory activity in human keratinocytes.

Croft foresees a future for TWEAK inhibitors as therapies for a range of skin diseases such as psoriasis and atopic dermatitis (eczema) that have underlying commonalities. “We think TWEAK is involved in skin inflammation in general,” says Croft. His lab is currently investigating the role of TWEAK in eczema.

The study was funded by the U.S. National Institutes of Health.

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