A combined role for TNFR1 and IFNAR1 in psoriasis?

Introduction Psoriasis is a chronic inflammatory skin disease affecting 2–3 percent of the world population. The disease is mainly characterized by epidermal hyperplasia, scaling and erythema. But it is also associated with a high degree of morbidity and patients suffer from the social impact of the disease. In addition, the existing long-term medications come with side effects. The disease forms therefore a major burden for health care systems and society. Until now, the underlying mechanism is extensively studied since the etiology of psoriasis is poorly understood and remains to be investigated. A prominent role for TNF in the disease development of psoriasis has been shown. So far, various types of TNF antagonists have been developed, e.g. infliximab and etanercept. Additionally, more recently, type I interferons have also gained interest as potential drug targets in psoriasis. In our research, we are interested in targeting the receptors of TNF and type I IFN, namely TNFR1 and IFNAR1. We believe that targeting the receptors of these cytokines is at least equally efficient as targeting the ligands themselves. We also believe that by this approach, the specificity of the therapy increases and subsequently less side effects are expected to occur. Methods For this purpose, we have generated mice lacking either TNFR-receptor-1 (TNFR1-/-) or type I IFN-receptor-1 (IFNAR1-/-) on a C57BL/6 J background. Mice received a daily topical dose of 62.5 mg of imiquimod (IMQ) cream (Aldara) on the shaved back for 5 consecutive days. Wild type littermates received a similar treatment. Erythema and scaling were scored on a daily basis and on the last day, mice were euthanized and skin was isolated for histological analysis. Results We found that TNFR1-/- mice suffered less from imiquimod-induced erythema and scaling. Histological analysis of skin epidermis showed less hyperplasia, characterized by a reduced epidermal thickness, compared to their wild type littermates. Similar results were obtained for the IFNAR1-/- mice. Conclusion Mice lacking either the TNFR1 or IFNAR1 are protected against imiquimod-induced psoriasis. Both knockout mice show reduced erythema, scaling and epidermal thickness. Our data suggest that TNFR1 and IFNAR1 are potential drug targets in psoriasis and raise the question whether blocking both receptors might result in an even stronger protection. To investigate this, we have generated double knockout mice lacking both TNFR1 and IFNAR1. Our next goal is to test these mice in the imiquimod-induced psoriasis model and investigate whether we observe a synergistic protection against the insult. If we can prove that these mice have an increased resistance, then we can argue that the next step in treating psoriasis is combined inhibition therapy.