Mechanisms of immune-epithelial crosstalk in tissue repair

项目摘要 皮肤作为与外界的主要屏障，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慢性炎症的形成。 无法愈合的伤口，影响了超过2%的西方人口，估计花费了250亿美元， 每年管理。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是最佳修复所必需的。然而，在我们的国家中， 了解免疫细胞是如何被激活的，以及它们是如何与上皮细胞相互作用的， 直接修复。 正常皮肤包含无数的"自我平衡"免疫细胞类型，它们在皮肤组织中积极巡逻， 我们发现，健康的神经元和神经元被迅速激活，并被招募到受伤部位。其中包括17型免疫细胞 在过去的10年中才发现的子集和修复的整体功能尚未研究， 免疫活性动物。我们系统地消融了每种17型细胞类型，以确定它们在激活 伤口边缘上皮中发现17型-γ δ T细胞，而不是其他亚群是绝对必需的 用于伤口上皮再生这种串扰由原型细胞因子IL-17 A/F信号直接介导 通过它们的受体IL-17 RC进入上皮。令人惊讶的是，我们发现IL17RC信号激活HIF 1a， 蛋白质，并且该信号传导轴是伤口边缘最佳HIF 1a活化所需的，即使在预处理中也是如此。 缺氧。上皮HIF1a的缺失严重破坏了伤口的再上皮化，这表明这种跨膜作用可能是一种新的治疗方法。 转录因子是伤口边缘上皮活化的主要调节因子。虽然17-γ δ T细胞具有 尽管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，IL 17信号转导究竟如何诱导HIF 1a尚不清楚， 修理需要说明。 我们将在两个独立的目标中解决这些基本问题：（1）17型-γ δ T细胞是如何被 在伤口的上皮再生前沿被激活（2）炎症性HIF1a是如何控制复发的？ IL-17下游的上皮形成程序？解码创伤相关组织之间的分子相互作用， 活化的淋巴细胞和边缘上皮细胞，正如我们在这里提出的，是寻找免疫- 慢性不愈合伤口的基础疗法。此外，许多炎症性疾病和癌症， 通过17型免疫，CO-OPT具有伤口修复功能。因此，我们的研究不仅将揭示基本机制， 免疫-上皮串扰的修复，但也可能提供新的治疗靶点的范围内， 17型免疫介导的上皮病变。

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.