Investigation of immunoregulatory functions of the antimicrobial peptide RNase 7

抗菌肽RNase 7的免疫调节功能研究

• 批准号: 364100506
• 负责人: Professor Dr. Jürgen Harder
• 金额: --
• 依托单位: Klinik für Dermatologie, Venerologie und Allergologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/364100506?language=en
• 关键词: Investigation; immunoregulatory; functions; antimicrobial; peptide

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.

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。抗微生物核糖核酸酶由人角质形成细胞组成型表达。它的表达被微生物和促炎细胞因子进一步上调，并且已经发现在患有慢性炎性皮肤病如特应性皮炎和银屑病的患者的病变皮肤中增强。我们自己的初步工作确定了RNase 7对人TH 2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RNase 7介导的TH 2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。这些观察结果指出了RNase 7在调节皮肤中的先天性和适应性免疫应答中的重要作用，以及RNase 7用于治疗特应性皮炎和病毒性皮肤感染的可能治疗益处。本研究在前期工作的基础上，详细研究RNase 7对人TH 2细胞和角质形成细胞的免疫调节功能，揭示其作用机制，并探索新的免疫调节功能。特别地，将用来自健康供体的细胞和器官型皮肤模型与患有银肩病和特应性皮炎的供体进行比较，研究RNA酶7介导的角质形成细胞的自分泌激活，重点是RNA酶7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/淋巴细胞共培养物、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。