Induced Psoriasis in Mice Suggests a Role for Jun

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Induced Psoriasis in Mice Suggests a Role for Jun

Knocking out expression of the JunB gene in mouse epidermal cells led to a psoriasis-like condition in the skin and joints.

For years, people have debated whether psoriasis is fundamentally a disorder of the skin or of the immune system. The clinical benefit of immunosuppressants and anti-TNF therapies for psoriasis suggests that T cells and TNF signaling are essential factors in development of this disorder, but a recent report brings psoriasis back to the skin.

Zenz and colleagues found that a set of transcription factors -- JunB and c-Jun -- was differentially expressed in human psoriatic lesions; specifically, JunB expression was lost and c-Jun expression was greater. The Jun factors are components of the AP-1 transcription factor, which has been implicated in cellular proliferation, differentiation, and stress response.

To better define the contribution of these factors, the investigators generated mice whose skin (only) was deficient in JunB, c-Jun, or both. The loss of either Jun gene produced minimal skin findings, but when both genes were deleted, a pronounced psoriasis-like condition developed, most frequently on the ears, paws, and tail. The skin condition was accompanied by arthritis, a common clinical feature in human psoriasis, and the cytokine profile of the mouse lesions paralleled profiles in human psoriasis.

The investigators then compared reactions in Jun-deficient mice with and without T cells or TNF receptors. Surprisingly, the absence of T cells and TNF signaling did not inhibit the development of cutaneous lesions, although the arthritis component was greatly reduced.

Comment: These results suggest that an epidermis-specific molecular defect defined by loss of both JunB and c-Jun is sufficient to induce mouse lesions bearing histologic resemblance to human psoriasis. The absence of T-cell participation in this psoriasis model is certainly interesting and puts the mechanism ball back in the immunologists' court. Conceivably, there are initiation and amplification phases in the immunologic response, with T cells unnecessary in the early phases. However, the necessity of TNF signaling to the development of arthritis in these mice is consonant with the great response of psoriatic arthritis to anti-TNF biologics. This disease model is clearly only one possibility in a heterogeneous condition, and further studies are needed to clarify the role of Jun transcription factors in human psoriasis.

— Hensin Tsao, MD, PhD

Published in Journal Watch Dermatology October 25, 2005