Mechanisms of immune-epithelial crosstalk in tissue repair

项目总结 皮肤是通往外部世界的主要屏障，因此经常受伤。因此，快速修复 组织损伤对生物体的生存至关重要。不能修复伤口会导致慢性或 无法愈合的伤口，影响着超过2%的西方人口，估计耗资250亿美元 每年管理一次。免疫抑制是慢性伤口形成的一个主要易感因素，表明 来自免疫细胞的信号是最佳修复所必需的。然而，在我们的国家中有一个很大的差距 了解免疫细胞究竟是如何被激活的，以及它们究竟是如何与上皮细胞相互作用的 直接修复。 正常皮肤由无数种“动态平衡”免疫细胞组成，它们活跃地在皮肤组织中巡逻。 健康和我们发现是迅速激活和招募到受伤的地方。这些细胞包括17型免疫细胞 最近10年才发现的子集和修复中的整个功能尚未在 具有免疫能力的动物。我们系统地消融了每种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型γδ中，T细胞是绝对必要的，而不是其他亚群 用于伤口再上皮化。这种串扰是由典型的细胞因子IL-17A/F信号直接介导的 通过其受体IL-17RC进入上皮细胞。令人惊讶的是，我们发现IL17RC信号激活了HIF1a 蛋白质，而这个信号轴是伤口边缘最佳HIF1a激活所必需的，即使在压力下- 缺氧的征兆。上皮性HIF1a的丢失深刻地破坏了伤口的再上皮化，表明这一转导- 转录因子是伤口边缘上皮细胞活化的主要调节因子。而17-γδT细胞 尽管已经在病原体反应中进行了研究，但它们如何在伤口中被招募和激活却知之甚少。 此外，IL17信号如何诱导HIF1a的确切机制尚不清楚，以及驱动HIF1a的分子靶点 修复需要澄清。 我们将通过两个独立的目标来解决这些基本问题：(1)17-γδT细胞是如何 (2)炎症性HIF1a是如何控制伤口再上皮化的？ IL-17下游的上皮化计划？破译创伤-关联-之间的分子相互作用- 淋巴细胞和边缘上皮，正如我们在这里提出的，是寻找免疫的重要第一步- 以慢性不可愈合伤口为基础的治疗。此外，许多炎症性疾病和癌症， 通过17型免疫，Coopt以伤口修复为特色。因此，我们的研究不仅将发现基本的机械-- 修复中的免疫-上皮串扰，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。

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.