The Role of Plakophilin 1 in Inflammatory Signaling

Plakophilin 1 在炎症信号传导中的作用

• 批准号: 404288583
• 负责人: Dr. René Keil
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/404288583?language=en
• 关键词: Role; Plakophilin; Inflammatory; Signaling

The skin provides a life sustaining barrier to protect the host against various environmental insults. The skin mechanically limits water loss, prevents the entry of potentially damaging agents and is a constituent of the immune system. Disturbed barrier function contributes to the pathogenesis of skin diseases like psoriasis, atopic dermatitis and also cancer. The keratinocytes, the main cell type of the mammalian epidermis, facilitate barrier formation through their strong intercellular cohesion, provided by desmosomes. The loss of desmosomal cohesion as provoked by several autoimmune, genetic and microbial diseases that target desmosomal components are accompanied by chronic inflammations, disordered wound healing and multiple allergies. Although the contribution of the impaired barrier to these phenotypes is unquestionable, increasing evidence suggests a keratinocyte-intrinsic function of desmosomal proteins in regulating inflammatory responses. In this context the multifunctional plakophilin 1 (PKP1), which is essential for stable desmosomal cohesion and has also been described to regulate mRNA-metabolism, translation and proliferation, might play a central role. Loss-of-function mutations of PKP1 cause the rare but severe epidermal dysplasia skin fragility syndrome (EDSFS) characterized by skin erosions and accompanied by erythema, chronic perioral inflammation and recurrent skin infections.My preliminary data reveal an excessive inflammatory response in the skin of PKP1 knockout mice as well as in keratinocytes derived from these animals. PKP1 knockout keratinocytes secrete increased amounts of the primary response cytokines CXCL1 and IL-1α in the absence of exogenous inflammatory triggers. Upon poly I:C stimulation, used to mimic viral infections, the production of TNF-α, IL-6 as well as CXCL1 and IL-1α is strongly induced or further increased and exceeds the level of wildtype keratinocytes by a multiple. Elevated cytokine secretion correlates with elevated mRNA-levels and increased NFκB-activity, suggesting that PKP1 is required to dampen inflammatory responses by influencing inflammatory signaling pathways.In order to elucidate the molecular basis of this phenotype in PKP1 knockout mice and keratinocytes, and explain the multiple symptoms described for EDSFS, I want to decipher:(1) How does PKP1 regulate the transcription of primary response cytokines?(2) What are the consequences that arise from PKP1-dependent dysfunctional inflammatory responses? Taken together, this study will reveal the molecular basis for the role of PKP1 during inflammatory processes. Moreover, it will provide a profound basis for future investigations addressing the role of PKP1 in wound healing processes as well as inflammatory skin diseases and unravelling the pathways that modulate the versatile functions of PKP1.

皮肤提供维持生命的屏障以保护宿主免受各种环境侵害。皮肤机械地限制水分流失，防止潜在的破坏性物质进入，并且是免疫系统的组成部分。屏障功能紊乱有助于皮肤病如牛皮癣、特应性皮炎以及癌症的发病机制。角质形成细胞是哺乳动物表皮的主要细胞类型，通过桥粒提供的强细胞间粘附促进屏障形成。由靶向桥粒组分的几种自身免疫性、遗传性和微生物疾病引起的桥粒凝聚力的丧失伴随着慢性炎症、创伤愈合紊乱和多种过敏。虽然这些表型的障碍受损的贡献是毋庸置疑的，越来越多的证据表明，角质形成细胞内在的功能的桥粒蛋白在调节炎症反应。在这种情况下，多功能的plakophilin 1（PKP 1），这是必不可少的稳定桥粒凝聚力，也被描述为调节mRNA的代谢，翻译和增殖，可能发挥核心作用。PKP 1基因的功能缺失突变导致罕见但严重的表皮发育不良性皮肤脆性综合征（EDSFS），其特征是皮肤糜烂并伴有红斑、慢性口周炎症和复发性皮肤infections.My初步数据显示，PKP 1基因敲除小鼠的皮肤以及来自这些动物的角质形成细胞中存在过度的炎症反应。PKP 1敲除的角质形成细胞在没有外源性炎症触发物的情况下分泌增加量的初级应答细胞因子CXCL 1和IL-1α。在用于模拟病毒感染的poly I：C刺激后，TNF-α、IL-6以及CXCL 1和IL-1α的产生被强烈诱导或进一步增加，并超过野生型角质形成细胞的水平数倍。细胞因子分泌增加与mRNA水平升高和NFκ B活性增加相关，提示PKP 1通过影响炎症信号通路来抑制炎症反应，为了阐明PKP 1敲除小鼠和角质形成细胞中这种表型的分子基础，并解释EDSFS的多种症状，我想解释：（1）PKP 1如何调节初级反应细胞因子的转录？(2)PKP 1依赖性功能失调性炎症反应的后果是什么？总之，这项研究将揭示PKP 1在炎症过程中作用的分子基础。此外，它将为未来的研究提供深刻的基础，解决PKP 1在伤口愈合过程中的作用以及炎症性皮肤病，并解开调节PKP 1多功能的途径。