Psoriasis is a common heterogeneous inflammatory skin disease with a complex pathophysiology and limited treatment options. Here we performed proteomic analyses of human psoriatic epidermis and found S100A8-S100A9, also called calprotectin, as the most upregulated proteins, followed by the complement component C3. Both S100A8-S100A9 and C3 are specifically expressed in lesional psoriatic skin. S100A9 is shown here to function as a chromatin component modulating C3 expression in mouse and human cells by binding to a region upstream of the C3 start site. When S100A9 was genetically deleted in mouse models of skin inflammation, the psoriasis-like skin disease and inflammation were strongly attenuated, with a mild immune infiltrate and decreased amounts of C3. In addition, inhibition of C3 in the mouse model strongly reduced the inflammatory skin disease. Thus, S100A8-S100A9 can regulate C3 at the nuclear level and present potential new therapeutic targets for psoriasis.

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Inflammation is a physiological response of the body to tissue injury, pathogen invasion and irritants. In the course of inflammation, immune cells of the innate and/or adaptive immune system are activated and recruited to the site of inflammation. Attraction and activation of immune cells is regulated by a variety of different cytokines and chemokines, which are predominantly regulated by transcription factors such as AP-1, NF-κB, NFATs and STATs. The evidence that Jun/AP-1 proteins control inflammation in the skin is summarised in this article. Genetic mouse models have demonstrated that a loss of Jun/AP-1 expression in epidermal cells controls cytokine expression through transcriptional and post-transcriptional pathways. The absence of JunB in epithelial K5-expressing tissues leads to a multiorgan disease, which is characterised by increased levels of granulocyte colony-stimulating factor and interleukin 6. Deletion of both JunB and c-Jun, in a constitutive or inducible manner, leads to perinatal death of newborn pups and to a psoriasis-like disease in adults, in which tumour necrosis factor α and the TIMP-3/TACE pathway have central roles. The loss or reduction of Jun expression in the epidermis relieves a block on cytokine expression. As a consequence, the increased levels of cytokines in mice lead to diseases reminiscent of psoriasis and systemic lupus erythematosus in human patients. New targets identified in mouse models, together with investigations on human samples, will provide important new avenues for therapeutic interventions in psoriasis and other inflammatory skin diseases.

Psoriasis is a common inflammatory skin disease of unknown etiology, for which there is no cure. This heterogeneous, cutaneous, inflammatory disorder is clinically characterized by prominent epidermal hyperplasia and a distinct inflammatory infiltrate. Crosstalk between immunocytes and keratinocytes, which results in the production of cytokines, chemokines and growth factors, is thought to mediate the disease. Given that psoriasis is only observed in humans, numerous genetic approaches to model the disease in mice have been undertaken. In this Review, we describe and critically assess the mouse models and transplantation experiments that have contributed to the discovery of novel disease-relevant pathways in psoriasis. Research performed using improved mouse models, combined with studies employing human cells, xenografts and patient material, will be key to our understanding of why such distinctive patterns of inflammation develop in patients with psoriasis. Indeed, a combination of genetic and immunological investigations will be necessary to develop both improved drugs for the treatment of psoriasis and novel curative strategies.