Investigation of immunoregulatory functions of the antimicrobial peptide RNase 7

核糖核酸酶7是角质形成细胞分泌的主要抗菌肽之一，具有很强的广谱抗菌活性。该抗菌核糖核酸酶由人角质形成细胞结构性表达。它的表达受到微生物和促炎细胞因子的进一步上调，并已被发现在特应性皮炎和牛皮癣等慢性炎症性皮肤病患者的皮损中增强。我们自己的初步工作证实了RNase7对人TH2细胞、浆细胞样树突状细胞和角质形成细胞的免疫调节作用，特别是RNase7介导的TH2细胞因子的下调和RNase7诱导的与皮肤抗病毒反应相关的I型干扰素的上调。这些观察结果表明，RNase7在调节皮肤的先天和获得性免疫反应方面发挥了重要作用，并可能对特应性皮炎和病毒性皮肤感染的治疗有好处。在我们前期工作的基础上，本研究的目的是详细研究RNase7对人TH2细胞和角质形成细胞的免疫调节功能，揭示其潜在的机制，并鉴定新的免疫调节功能。特别是，RNase7介导的角质形成细胞的自分泌激活将通过来自健康捐赠者的细胞和器官型皮肤模型进行研究，并与银屑病和特应性皮炎的捐赠者进行比较，重点是RNase7在人角质形成细胞中诱导抗病毒防御反应。此外，将在角质形成细胞/淋巴细胞共培养、器官型皮肤模型和体外皮肤中研究已确定的免疫调节功能的相关性。更好地了解RNase7在炎症性和病毒性皮肤病发病机制中的作用可能有助于开发基于RNase7的治疗策略。

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.