Understanding the Molecular Basis of Psoriasis

Psoriasis is s an autoimmune disease that often appears on the skin. It occurs when the immune system sends out faulty signals that speed up the growth cycle of skin cells. The most common form, plaque psoriasis, is commonly seen as red a scaly patches appearing on the top layer of the skin.

Psoriasis is s an autoimmune disease that often appears on the skin. It occurs when the immune system sends out faulty signals that speed up the growth cycle of skin cells. The most common form, plaque psoriasis, is commonly seen as red a scaly patches appearing on the top layer of the skin.

Unsightly red patches, itchy, flaky skin, and disfigured nails are typical symptoms of psoriasis, one of the most common chronic inflammatory diseases of the skin. An estimated 7.5 million people in the United States are affected. The disease is characterized by increased production of skin cells and inflammation in the skin, but it is unclear if the primary trigger is dysregulation of the immune system, abnormalities in skin cells, or both.

As the disease tends to run in families, scientists looked for genes that may make people susceptible to psoriasis. Genetic analysis indicated that both genes encoding immune function and those encoding skin cell function are implicated in susceptibility to psoriasis and increased psoriasis lesions. Skin of people with this genetic predisposition is prone to forming inflammatory lesions in response to environmental triggers and mechanical damage. Despite these recent findings, the functional link between external triggers and development of full-blown psoriasis remains elusive.

Stuart H. Yuspa, M.D., of the CCR Laboratory of Cancer Biology and Genetics, and a team of other CCR scientists and international collaborators sought to understand the interplay between external stimulus, skin cell growth, and inflammation in psoriatic skin. His research team focused on proteins called S100A7 (psoriasin) and S100A15 (koebnerisin), which are encoded on a psoriasis susceptibility locus on human chromosome 1q21. Production and release of the two proteins are increased in psoriatic skin cells. The proteins are involved in launching an immune defense reaction and increasing inflammation.

To determine how the two proteins contribute to inflammation in psoriatic skin, Yuspa and colleagues created a genetically modified mouse model that makes large amounts of a mouse version of S100A7/S100A15 in the epidermis, mimicking skin conditions in human psoriasis. As expected, the skin of the engineered mouse reacted with an exaggerated inflammatory response when it was exposed to a chemical irritant or mechanically wounded (exfoliation). Further, the mouse’s skin cells had elevated levels of Th1 and Th17 cytokines, the same pro-inflammatory molecules that are considered critical for development and maintenance of psoriatic lesions in people. S100A7/S100A15 also increased inflammation by attracting immune cells to the skin. Molecular analysis revealed that the heightened inflammatory response required interaction of S100A7/S100A15 with a receptor protein called RAGE.

The study, which appears in the journal Science Translational Medicine, suggests that elevated levels of S100A7 and S100A15 proteins increase the skin’s sensitivity to inflammation in response to external stimuli. The fact that elevated expression of those proteins was a sufficient prerequisite for development of inflammatory psoriatic lesions in the mouse model suggests that the two proteins potentially play a critical role in human disease. The S100A7/S100A15-RAGE axis may be a useful target for new drugs to treat psoriasis.

Summary Posted: 01/2011

Reference

Sci Transl Med 8 December 2010: Vol. 2, Issue 61, p. 61ra90 DOI: 10.1126/scitranslmed.3001108. Reviewed by Donna Kerrigan PubMed Link