Understanding immune-epithelial interactions during wound repair in live mammals

摘要 慢性伤口的治疗会带来很大的医疗负担，但基本上是无效的。此外, 慢性伤口长时间的皮肤屏障缺陷会导致感染或发展成更严重的疾病。 比如癌症。因此，迫切需要了解追回 伤口修复过程中的皮肤屏障，以开发有效的治疗方法，防止疾病的进展。皮肤 表皮(即最外层的皮肤)是我们身体的屏障，由不同类型的 细胞：表皮复层上皮中的上皮细胞起到物理屏障的作用，而皮肤网络- 常驻免疫细胞朗格汉斯细胞(LCS)起到免疫屏障的作用。LCS监视皮肤表面，如 免疫哨兵，可诱导免疫和耐受。尽管LCS的免疫功能具有 已被彻底研究，其他免疫细胞(如巨噬细胞和中性粒细胞)已知在 关于LCS在皮肤再生中的作用，人们对LCS在皮肤再生中的作用知之甚少。我们的长期目标是 了解调节皮肤再生和修复的基本机制。这样做的目的是 建议更深入地了解LC-上皮细胞相互作用，以恢复完好的皮肤屏障 活着的哺乳动物。这将为急慢性伤口修复提供信息并推动新的治疗策略。我们 将测试LC在重新上皮化过程中与上皮细胞的行为，并重新构建受损的网络 使用我们的活体成像系统的活老鼠。在这个项目完成后，我们将了解LCS，在 与邻近的上皮细胞结合，在伤口修复过程中有助于皮肤再生。我们的工作 提示LC和上皮细胞相互沟通，以维持表皮内环境的稳定。 值得注意的是，伤口附近激活的LC显示出明显的转录信号，可以调节 上皮细胞的行为。我们最近观察到伤口附近激活的LC与上皮细胞一起迁移 在再上皮化过程中。这些LC最终迁移到伤区，并有助于创伤的恢复 具有单核细胞来源的LC的LC网络。这一发现使我们假设激活的 损伤表皮中的LC和上皮细胞对于LC网络的再上皮化和恢复是必不可少的。 为了解决这一假设，我们将确定LCS如何调节影响再上皮化的上皮行为。 接下来，我们将测试LC和上皮细胞之间的相互作用如何影响LCS的流动性和监视 LCS在重新上皮化过程中。最后，我们将阐明不同来源的LC如何合作重建新的 LC在受伤区域内形成网络，以恢复皮肤完整的免疫屏障。来自我们的见解 拟议的工作将为在再生医学治疗中利用LCS的力量提供基础 慢性伤口。

SUMMARY Treatments for chronic wounds incur a substantial healthcare burden, but are largely ineffective. In addition, prolonged skin barrier defects in chronic wounds can cause infection or develop into even more severe diseases such as cancer. Therefore, there is a critical need to understand the mechanisms involved in the recovery of the skin barrier during wound repair to develop effective treatments and prevent progression of disease. The skin epidermis (i.e., outermost layers of skin) serves as a barrier to our body and is composed of different types of cells: epithelial cells in the stratified epithelium of the epidermis act as a physical barrier, and a network of skin- resident immune cells, Langerhans cells (LCs), act as an immunological barrier. LCs surveil the skin surface as immune sentinels and can induce both immunity and tolerance. Although immunological functions of LCs have been thoroughly investigated, and other immune cells (e.g., macrophages and neutrophils) are known to play a role in skin regeneration, little is known about the role of LCs in skin regeneration. Our long-term goal is to understand the fundamental mechanisms that regulate skin regeneration and repair. The objective of this proposal is to gain a deeper understanding of LC-epithelial cell interactions that restore an intact skin barrier in live mammals. This will inform and advance new therapeutic strategies for acute and chronic wound repair. We will test how LCs behave with epithelial cells during re-epithelization and rebuild a damaged network de novo in live mice using our intravital imaging system. Upon completion of this project, we will understand how LCs, in conjunction with neighboring epithelial cells, contribute to skin regeneration during wound repair. Our work suggests that LC and epithelial cells communicate with each other to maintain epidermal homeostasis. Remarkably, activated LCs near the wound show distinct transcriptomic signatures that can regulate the behaviors of epithelial cells. We recently observed that activated LCs near the wound migrate with epithelial cells during re-epithelization. These LCs eventually migrate to the wounded area and contribute to the recovery of the LC network with monocyte-derived LCs. This finding led us to hypothesize that communication between activated LCs and epithelial cells in the injured epidermis is essential for re-epithelization and recovery of the LC network. To address this hypothesis, we will determine how LCs regulate epithelial behaviors that impact re-epithelization. Next, we will test how the interactions between LCs and epithelial cells affect the mobility and surveillance of LCs during re-epithelization. Finally, we will elucidate how LCs of different origins cooperatively reestablish new LC networks within the wounded area to restore an intact immune barrier of the skin. The insights from our proposed work will provide the foundations to harness the power of LCs in regenerative medicine for treating chronic wounds.