Fibroblast dysregulation promotes dermal eosinophilic/Th2 inflammation

摘要：特应性皮炎(AD)是最常见的炎症性皮肤病之一，据估计 在成人中的患病率接近5%，典型的特征是儿科发病、瘙痒和顽固性。 研究表明，阿尔茨海默病与上皮屏障受损有关，该屏障促进对 环境抗原和II型免疫反应。尽管AD研究取得了进展，但致病因素 (S)导致持久型免疫应答的机制尚不清楚。我们最近的出版物和 PREL数据表明，真皮和皮下组织中含有似乎与类型建立有关的成纤维细胞 II皮肤中的炎症反应。了解皮肤成纤维细胞的失调是如何导致 它们可能引发炎症性AD样病变形成的下游事件是这一点的焦点 求婚。 我们的PREL数据显示，在PRX1+成纤维细胞中，核因子-kB信号的失调导致CEBPB上调 在成纤维细胞中，CCL11表达上调，组织嗜酸性粒细胞增多，随后出现与人类相似的II型皮肤病变 广告。我们的小鼠模型与人类AD样病变有许多相似之处，包括真皮和 组织学、细胞和分子水平的表皮。PREL数据将单细胞RNAseq分析与 我们的研究使用了已发表的人类AD病变的scRNAseq数据库。我们模型的scRNAseq分析和 人AD的成纤维细胞表达异常，涉及CCL11和CEBPB。此外，使用RNAScope，我们还拥有 结果显示，经过验证的人类AD样本中含有大量共表达CEBPB的真皮成纤维细胞 与CCL11对照的人皮肤，也符合我们的小鼠模型。因此，我们建议 新的临床前和翻译研究(目标1)，以确定成纤维细胞 CEBPB介导的调节失调诱导了这些细胞的炎症表型。目标2将决定 嗜酸性粒细胞在AD样皮肤中作为触发II型免疫反应的关键中间体的作用。目标 3将使用空间转录学(GeoMX)和RNA序列来探索人类成纤维细胞中的相同机制 以及AD样本和使用抑制剂作为AD潜在治疗方法的翻译研究。我们期待着 建议的研究和文献中的最新报告有助于理解范式的转变 与成纤维细胞调节失调相关的AD发病机制及新疗法的开发 可能会阻止AD发展的干预措施。

Abstract: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with an estimated prevalence approaching 5% in adults and is typically characterized by pediatric onset, pruritis and persistance. Research has indicated that AD is associated with an impaired epithelial barrier that promotes sensitization to environmental antigens and a type II immune response. Despite advances in AD research, the causative mechanism(s) leading to the persistent type II immune response remain unclear. Our recent publication and Prel Data indicate that the dermis and subcutis contain fibroblasts that appear to be involved in establishing type II inflammatory reactions in skin. Understanding how dysregulation of skin fibroblasts contributes to downstream events that they may intitiate formation of inflammatory AD-like lesions is the focus of this proposal. Our Prel Data show that dysregulation of NF-kB signaling in Prx1+ fibroblasts leads to upregulation of CEBPb in fibroblasts, upregulation of CCL11 and tissue eosinophilia followed by type II skin lesions resembling human AD. Our mouse model shares many similarities with human AD-like lesions involving both the dermis and epidermis at the histologic, cellular and molecular levels. Prel Data compares single cell RNAseq analysis from our study with published scRNAseq databases from human AD lesions. scRNAseq analysis from our model and human AD show fibroblast dysregulation involving CCL11 and CEBPb. Moreover, using RNAScope we have also shown that validated human AD samples contain increased numbers of dermal fibroblasts co-expressing CEBPb and CCL11 compared to matched control human skin, also consistent with our murine model. Thus, we propose novel preclinical and translational studies (Aim 1) to define molecular mechanisms by which fibroblast dysregulation mediated by CEBPb induces an inflammatory phenotype in these cells. Aim 2 will determine the role of eosinophil infiltration as a key intermediate for triggering type II immune response in AD-like skin. Aim 3 will use spatial transcriptomics (GeoMX) and RNA seq to explore equivalent mechanisms in human fibroblasts and AD specimens and translational studies using inhibitors as potential treatments for AD. We expect the proposed studies along with recent reports in the literature to contribute to a paradigm shift in understanding AD pathogenesis regarding fibroblast dysregulation and contribute to development of new therapeutic interventions that may prevent the development of AD.