Investigation of immunoregulatory functions of the antimicrobial peptide RNase 7

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RNase 7 is one of the major antimicrobial peptides secreted by keratinocytes and exhibits a strong broad spectrum antimicrobial activity. The antimicrobial ribonuclease is constitutively expressed by human keratinocytes. Its expression is further up-regulated by microorganisms and proinflammatory cytokines and has been found to be enhanced in lesional skin of patients with chronic inflammatory skin diseases such as atopic dermatitis and psoriasis. Our own preliminary work identified immunoregulatory effects of RNase 7 on human TH2 cells, plasmacytoid dendritic cells and keratinocytes, in particular a RNase 7-mediated down-regulation of TH2 cytokines and a RNase 7-induced up-regulation of type I interferons associated with a cutaneous antiviral response. These observations point to an important role of RNase 7 in the regulation of innate and adaptive immune responses in the skin and to a possible therapeutic benefit of RNase 7 for the treatment of atopic dermatitis and viral skin infections. Based on our preliminary work the aim of this study is to investigate the immunoregulatory functions of RNase 7 on human TH2 cells and keratinocytes in detail, to uncover the underlying mechanisms and to identify new immunoregulatory functions. In particular, the RNase 7 mediated autocrine activation of keratinocytes will be studied with cells and organotypic skin models from healthy donors compared to donors with psoriasis and atopic dermatitis with focus on the induction of an antiviral defense response in human keratinocytes by RNase 7. Furthermore, the relevance of the identified immunoregulatory functions will be investigated in keratinocyte / lymphocyte co-cultures, organotypic skin models and ex vivo skin. A better understanding of the role of RNase 7 in the pathogenesis of inflammatory and viral skin diseases may help to develop RNase 7-based therapeutic strategies.