The Role of Plakophilin 1 in Inflammatory Signaling

皮肤提供了一种维持生命的屏障，以保护宿主免受各种环境侮辱。皮肤机械地限制水分流失，防止潜在的破坏性因素进入，是免疫系统的组成部分。屏障功能紊乱导致牛皮癣、特应性皮炎和癌症等皮肤病的发病。角质形成细胞是哺乳动物表皮的主要细胞类型，通过桥粒提供的强大的细胞间粘附力促进屏障的形成。由几种针对桥粒成分的自身免疫、遗传和微生物疾病引起的桥粒凝聚力的丧失伴随着慢性炎症、伤口愈合障碍和多种过敏。尽管屏障受损对这些表型的贡献是毋庸置疑的，但越来越多的证据表明，桥粒蛋白在调节炎症反应中具有角质形成细胞的内在功能。在此背景下，多功能的血小板亲和素1(PKP1)，它是稳定的桥粒凝聚力所必需的，也被描述为调节mRNA的新陈代谢，翻译和增殖，可能发挥核心作用。PKP1功能缺失突变导致罕见但严重的表皮发育不良皮肤脆性综合征(EDSFS)，其特征是皮肤侵蚀，并伴有红斑、慢性口腔周炎和反复皮肤感染。我的初步数据显示，PKP1基因敲除小鼠的皮肤以及这些动物来源的角质形成细胞中存在过度的炎症反应。在没有外源性炎症诱因的情况下，蛋白酪氨酸激酶1基因敲除的角质形成细胞分泌大量的主要反应细胞因子CXCL1和IL-1α。在用来模拟病毒感染的Poly I：C刺激下，肿瘤坏死因子-α、IL-6以及CXCL1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水平数倍。为了阐明PKP1基因敲除小鼠和角质形成细胞中这种表型的分子基础，并解释κ综合征的多种症状，我想要解释：(1)PKP1如何调节初级反应细胞因子的转录？(2)依赖PKP1的功能障碍炎症反应产生的后果是什么？综上所述，这项研究将揭示PKP1在炎症过程中作用的分子基础。此外，它将为未来研究PKP1在伤口愈合过程中的作用以及炎症性皮肤病提供深刻的基础，并解开调节PKP1多种功能的途径。

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.