Understanding immune-epithelial interactions during wound repair in live mammals

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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.