Researchers Describe Role of Cell-Signaling Molecule in Psoriasis
Findings Reveal Potential Target for New Treatments
A new National Institutes of Health (NIH) study describes in mice how the cell-signaling molecule interleukin 17 (IL-17) contributes to the development of psoriasis, an inflammatory skin disease. NIH scientists found that a protein called CIKS, which is essential for IL-17 signaling, participates in disease-driving processes in different types of skin cells. Their results, reported in Proceedings of the National Academy of Sciences, suggest that CIKS may be a potential target for new drugs to treat psoriasis.
Illustration showing the differences between healthy and psoriatic skin.
Credit: FDA/Renée Gordon
Credit: FDA/Renée Gordon
Psoriasis is an autoinflammatory disorder that causes cells to build up rapidly on the skin’s surface, forming thick silvery scales and dry red patches that can be itchy or painful. In people with psoriasis, infection-fighting immune cells attack healthy skin cells. This triggers immune responses that lead to inflammation and increased production of skin cells. New skin cells are produced deep within the skin and differentiate into specialized cell types as they rise to the surface, a process that takes roughly a month in healthy skin. In psoriasis, the new skin cells rise within days and accumulate on the skin’s surface without properly differentiating. Another hallmark of psoriasis is an influx of immune cells to the skin. These cells release signaling molecules that contribute to inflammation and help recruit more immune cells.
Psoriasis affects an estimated 2 to 3 percent of people worldwide. Although treatments are available to manage the symptoms, many of these drugs cause side effects, can be expensive, and do not work for everyone with the disease. Researchers therefore are working to identify new treatment strategies.
Evidence suggests that IL-17 signaling plays a key role in the development of psoriasis, and results from early-stage clinical trials indicate that antibodies that neutralize IL-17 or its receptor can relieve psoriasis symptoms. In addition, studies have linked variations in the gene that produces CIKS to an increased risk of psoriasis.
Results of Study
To better understand how IL-17 and CIKS contribute to psoriasis, researchers led by Ulrich Siebenlist, Ph.D., of NIAID’s Laboratory of Molecular Immunology compared the development of psoriasis in normal mice and in mice lacking CIKS. When treated with an immune-activating compound, normal mice developed psoriatic plaques. The absence of CIKS greatly reduced plaque development, though did not completely eliminate all features of psoriasis, suggesting a key role for this protein in the disease.
The scientists found that CIKS signaling in keratinocytes, the cells that make up the outermost layer of the skin, contributes to the high skin cell production and lack of cell differentiation characteristic of psoriasis. Compared to normal mice, mice completely lacking CIKS, as well as mice lacking CIKS only in keratinocytes, did not produce as many extra cells, but had more differentiated cells.
CIKS also contributed to the accumulation of inflammatory cells, in particular IL-17-producing cells called γδT cells, in the skin. Mice completely lacking CIKS did not accumulate these cells. However, large numbers of γδT cells gathered in the skin of mice lacking CIKS in keratinocytes, indicating that CIKS signaling in other cell types promotes immune cell accumulation. In cell-culture experiments, the scientists pinpointed a certain cell type in the dermis (the layer of skin below the surface) that responds to IL-17 by releasing other cell-signaling molecules. These molecules stimulate γδT cells to produce more IL-17, perpetuating the cycle.
The study findings help clarify how IL-17 and CIKS contribute to psoriasis by acting on different types of skin cells, although further studies are needed to confirm that a similar process occurs in humans. The results also suggest that drugs that block the function of CIKS potentially could provide new treatment strategies for this chronic skin condition.
The researchers are planning experiments to investigate in greater detail how IL-17 signaling in keratinocytes increases production and reduces differentiation of skin cells. One of the team’s long-term goals is to identify small molecules that block CIKS. Ultimately, drugs targeting CIKS, which potentially could be applied directly to the skin, may offer an alternative to injectable antibody-based treatments targeting IL-17, which currently are being tested in late-stage clinical trials.
Ha H-L, Wang H, Pisitkun P, Kim J-C, Tassi I, Tang W, Morasso MI, Udey MC, Siebenlist U. IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1400513111 (2014).
This work was supported by the intramural research programs of NIAID, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Cancer Institute.