Mouse model, protein discovery advance psoriasis understanding

Through the development of a new mouse model, researchers discovered that the intracellular protein Stat3 is crucial to the development of psoriasis and that inhibiting Stat3 may be an effective therapeutic intervention in treating human psoriatic lesions. The mouse is the first animal model that recapitulates both the histologic and immunologic characteristics of human psoriasis.

Stat3, an intracellular transcription factor involved in signaling from the cell surface to the nucleus, plays a critical role in the proliferation, survival and migration of cells. It is a "master regulator" that can up or downregulate expression of a number of genes, says John DiGiovanni Ph.D., a researcher at the M.D. Anderson Cancer Center.

Dr. DiGiovanni has explored the role of Stat3 in tumor growth and wound healing in his ongoing research on skin carcinogenesis. Since a number of studies have implicated abnormal wound healing as a factor in the development of psoriatic lesions, Dr. DiGiovanni and his team of scientists investigated whether Stat3 might play a role in hyperproliferative skin diseases such as psoriasis.

Staining of tissue from chronic dermatitis, prurigo and lichen planus lesions produced patterns of Stat3 activation similar to those seen in normal skin.

"The data suggested that Stat3 might play a role in human psoriasis," he adds.

Dr. DiGiovanni's lab created a transgenic mouse that over-expresses a constitutively active form of Stat3.

"The mice developed scaly hyperkeratotic lesions on their tails, and on some mice those lesions would actually spread to the dorsal part of the skin. They would also get them on their feet. It occurred in all areas where there was physical abrasion, but not on other parts of their bodies," Dr. DiGiovanni explains.

"I remember looking at the first stained section of the tail, and our jaws dropped," Dr. DiGiovanni says. "They looked very much like human psoriatic lesions. We were pretty excited about that."

Administering a series of traumas - full thickness wounding, treatment with the skin tumor promoter TPA, even simple tape stripping - all induced full-blown psoriatic lesions on the skin of the transgenic mice within a few days. Those lesions shared histological features commonly found in human psoriatic lesions, including hyperkeratosis, parakeratosis, absence of granular layer, leukocyte infiltrates and dilated blood vessels in the papillary dermis.

"It made us think about the clinical features of human psoriasis - the Koebner phenomena - where trauma to the skin quite often elicits psoriatic lesions at the site of the trauma. Suddenly, the model had additional features similar to human psoriasis," he says.

Grafting skin Dr. DiGiovanni next grafted skin from the transgenic mice onto athymic nude mice. The tape-stripping test was not sufficient to generate psoriatic lesions. However, injecting the grafted skin with activated T-cells, combined with tape stripping, did produce psoriatic lesions.

"These results clearly show a requirement for both activated Stat3 in keratinocytes and activated T-cells in the dermis and epidermis for development of tape stripping-induced psoriatic lesions in mouse skin," Dr. DiGiovanni says.

Further studies showed that the T-cells found in psoriatic lesions induced in transgenic mice were primarily CD4⁺, expressing the early activation marker CD25 on their surface; there were few CD8⁺ cells.

The sequence of causative actions remains unclear in humans - whether infiltrating T-cells lead to activation of Stat3 in keratinocytes, or increased Stat3 in keratinocytes leads to infiltration of the T-cells.

"But the data show that, at least in our model, you have to have changes in both keratinocytes and in immune cell function in order to produce psoriatic lesions.

"These results have tremendous implications in terms of therapy and treatment, because trying to target immune function and immune cells is difficult. Now we have some specific things that we can focus on in keratinocytes," Dr. DiGiovanni says.