Mechanisms of immune-epithelial crosstalk in tissue repair

组织修复中免疫上皮串扰的机制

基本信息

批准号：
10565934
负责人：
Shruti Naik
金额：
$ 60.31万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-07 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10565934
关键词：
Ablation Activated Lymphocyte Address Affect Animals Autoimmune Binding Cancerous Cell Hypoxia Cells Chronic Communication Coupling Cytokine Signaling Cytotoxic T-Lymphocytes Data Dendritic Cells Dermal Epithelial Cells Epithelium Failure Genetic Transcription Goals Health Hypoxia IL17 gene Immune Immunity Immunocompetent Immunologist Immunosuppression Immunotherapy Impaired wound healing Impairment Inflammation Inflammatory Injury Interleukin Receptor Interleukins Intervention Knowledge Lymphocyte Lymphoid Cell Malignant Neoplasms Maps Measures Mediating Memory Molecular Molecular Target Mucous Membrane Mus Pathology Pathway interactions Population Positioning Attribute Predisposing Factor Production Proteins Regulatory T-Lymphocyte Resolution Risk Factors Role Science Signal Induction Signal Transduction Site Skin Specialist T-Cell Receptor T-Lymphocyte Techniques Technology Testing Thromboplastin Time Tissues cell type chronic wound cost estimate cytokine cytotoxic differential expression epithelial injury epithelial stem cell epithelial wound healing hypoxia inducible factor 1 in vivo injured innovation insight microbial migration mouse genetics new therapeutic target non-healing wounds novel pathogen programs prototype receptor recruit repaired response response to injury therapeutic target tissue repair transcription factor transcriptomics wound wound healing γδ T cells

项目摘要

PROJECT SUMMARY The skin serves as a primary barrier to the external world and is thus often injured. As such, rapid repair of tissue damage is vital for organismal survival. Failure to repair wounds results in the formation of chronic or non-healing wounds, which affect over 2% of the western population and cost an estimated 25 billion dollars to manage annually. Immunosuppression is one major predisposing factor to chronic wound formation, indicating that signals derived from immune cells are necessary for optimal repair. Yet, there is a significant gap in our understanding of exactly how immune cells are activated and precisely how they crosstalk with the epithelium to direct repair. Normal skin comprises a myriad of “homeostatic” immune cell types that actively patrol the tissue in health and we find are rapidly activated and recruited to the site of injury. These include type 17 immune cell subsets that have only been uncovered in the last 10 years and whole function in repair has not been studied in immunocompetent animals. We systematically ablated each type 17 cell type to determine their role in activating the wound edge epithelium and found that in type17-γδ T cells, but not other subsets are absolutely necessary for wound -re-epithelialization. This crosstalk is mediated by the prototypic cytokines IL-17A/F signaling directly into the epithelium via their receptor IL-17RC. Surprisingly, we uncovered that IL17RC signaling activates HIF1a protein, and that this signaling axis is required for optimal HIF1a activation at the wound edge even in the pres- ence of hypoxia. Loss of epithelial HIF1a profoundly disrupts wound re-epithelization indicating that this tran- scription factor is a master regulator of epithelial activation at the wounds edge. While type17-γδ T cells have been studied in pathogen responses, how they are recruited and activated in wounds is poorly understood. Additionally, exactly how IL17 signaling induces HIF1a is unclear and the molecular targets of HIF1a that drive repair require elucidation. We will address these fundamental questions in two independent aims: (1) How are type17-γδ T cells recruited to and activated at the wound’s re-epithelizing front? ; (2) How does inflammatory HIF1a control re- epithelialization programs downstream of IL-17? Decoding the molecular interactions between wound-associ- ated lymphocytes and would edge epithelium, as we propose here, is an essential first step in finding immune- based therapies for chronic non-healing wounds. Moreover, many inflammatory conditions and cancers, driven by type 17 immunity, co-opt features wound repair. Thus, our studies will not only unearth fundamental mecha- nisms of immune-epithelial crosstalk in repair, but may also provide novel therapeutic targets for a range of type17 immunity-mediated epithelial pathologies.

项目概要皮肤是外界的主要屏障，因此经常受伤，因此需要快速修复。组织损伤的修复对于生物生存至关重要。无法愈合的伤口，影响了超过 2% 的西方人口，估计花费 250 亿美元每年进行管理，免疫抑制是慢性伤口形成的一个主要诱发因素，表明来自免疫细胞的信号对于最佳修复是必要的，然而，我们的研究还存在重大差距。了解免疫细胞到底如何被激活以及它们如何与上皮细胞相互作用以直接修复。正常皮肤包含大量“稳态”免疫细胞类型，它们主动巡逻组织中的组织。我们发现，健康的细胞会被迅速激活并招募到受伤部位，其中包括 17 型免疫细胞。近 10 年来才发现的子集，并且尚未研究修复的整个功能我们系统地消除了每种 17 型细胞类型，以确定它们在激活中的作用。伤口边缘上皮，发现在 17-γδ T 细胞中，但不是其他亚群是绝对必要的这种串扰是由原型细胞因子 IL-17A/F 信号直接介导的。令人惊讶的是，我们发现 IL17RC 信号传导激活 HIF1a。蛋白质，并且这种最佳信号轴对于伤口边缘的 HIF1a 激活是必需的，即使在预缺氧的情况下，上皮细胞 HIF1a 的缺失会严重破坏伤口的再上皮化，这表明这种转变转录因子是伤口边缘上皮激活的主要调节因子，而 17-γδ T 细胞则具有这一功能。尽管人们对病原体反应进行了研究，但人们对它们如何在伤口中招募和激活知之甚少。此外，IL17 信号传导究竟如何诱导 HIF1a 以及驱动 HIF1a 的分子靶点尚不清楚。修复需要阐明。我们将通过两个独立的目标来解决这些基本问题：(1) 17-γδ T 细胞如何募集到伤口的上皮再生前沿并被激活？；（2）炎症性 HIF1a 如何控制再上皮化？ IL-17 下游的上皮化程序？解码伤口相关分子之间的相互作用正如我们在此提出的，活化的淋巴细胞和边缘上皮细胞是寻找免疫-的重要的第一步。此外，许多炎症和癌症也是由这种疗法引起的。通过 17 型免疫，co-opt 具有伤口修复功能，因此，我们的研究不仅会揭示基本机制。免疫上皮串扰在修复中的作用，但也可能为一系列疾病提供新的治疗靶点 17 型免疫介导的上皮病理学。