Role of the Transcription Factor NFATc1 in Psoriasis and Psoriasis-like Skin Inflammation

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Psoriasis is a common inflammatory skin disease affecting 2-3 % of the population that considerably impairs the quality of life. The disease is often associated with (psoriatic) arthritis, cardiovascular, metabolic and other co-morbidities. Scaling, infiltration and erythema are the clinical hallmarks of psoriasis, which reflect excessive proliferation and aberrant differentiation of keratinocytes as well as leukocyte infiltration of dermis and epidermis. Today, psoriasis is considered as a T cell-controlled systemic inflammatory disease that is modulated by genetic susceptibility and environmental factors. A cell type that -so far- has pathogenetically largely been neglected are B lymphocytes. Using a widely recognized mouse model of psoriasis-like skin inflammation that relies on the repetitive epicutaneous application of the Toll-Like Receptor (TLR)-7 agonist imiquimod (IMQ) we very recently showed that the absence of B lymphocytes resulted in a massive aggravation of skin inflammation. In contrast, mice with B lymphocyte-selective ablation of the transcription factor NFATc1 developed hardly any psoriasiform inflammation (Alrefai et al., Nature Communications 7:11724, doi: 10.1038/ncomms11724 (2016)). These observations could be attributed to the NFATc1-mediated transcriptional down-regulation of the anti-inflammatory cytokine interleukin-10 (IL-10) in B lymphocytes, which controlled Th1- and Th17-driven inflammation. The aim of this interdisciplinary project proposal is (i) to identify the developmental stages and (sub-) population(s) of B lymphocytes in which NFATc1 regulate(s) the development of murine skin inflammation and (ii) to elucidate whether and how B cells (including IL-10-producing regulatory B cells (Bregs)) affect the development and maintenance of psoriasis in humans. Moreover, we (iii) plan to elucidate the influence of NFATc1 on the metabolism of B lymphocytes and study its functional consequences in the context of skin inflammation. The work program will include cellular, molecular and immunological studies of genetically modified mice to identify relevant subpopulations of B lymphocytes and to systematically characterize NFATc1-regulated gene expression programs. Findings will be subsequently validated in lesional and non-lesional human psoriatic skin as well as in circulating lymphocytes of psoriasis patients and healthy controls. To finally proof the anticipated role of Bregs in human psoriasis, we will perform xenotransplantation of human psoriatic skin to SCID mice followed by the autologous adaptive transfer of human lymphocytes. Finally, we will study the effect of NFATc1 on the metabolism of lymphocytes to perspectively pave the way for novel therapeutic strategies for chronic skin inflammation such as psoriasis.