Investigation of immunoregulatory functions of the antimicrobial peptide RNase 7

RNase 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。抗菌核糖核酸酶由人角质形成细胞组成性表达。它的表达在微生物和促炎细胞因子的作用下进一步上调，在特应性皮炎、牛皮癣等慢性炎症性皮肤病患者的病变皮肤中被发现表达增强。我们自己的初步工作确定了RNase 7对人TH2细胞、浆细胞样树突状细胞和角化细胞的免疫调节作用，特别是RNase 7介导的TH2细胞因子的下调和RNase 7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，RNase 7在调节皮肤先天和适应性免疫反应中发挥重要作用，并可能在治疗特应性皮炎和病毒性皮肤感染方面发挥治疗作用。基于我们的前期工作，本研究的目的是详细研究RNase 7对人TH2细胞和角化细胞的免疫调节功能，揭示其潜在的机制，并发现新的免疫调节功能。特别是，RNase 7介导的角质形成细胞的自分泌激活将通过健康供体的细胞和器官型皮肤模型进行研究，并将其与牛皮癣和特应性皮炎供体进行比较，重点研究RNase 7诱导人角质形成细胞的抗病毒防御反应。此外，将在角质细胞/淋巴细胞共培养、器官型皮肤模型和离体皮肤中研究所鉴定的免疫调节功能的相关性。更好地了解RNase 7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RNase 7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.