Unraveling the Role of Langerhans Cells in Itch - PROJECT SUMMARY Chronic itch is a considerable medical challenge associated with various skin and systemic diseases, , exerting a profound impact on patients' overall quality of life. While the epidermis is conventionally considered the source of skin itch, critical knowledge gaps persist regarding the role of Langerhans cells (LCs), resident cells in the epidermis, in mediating itch. LCs play a vital immunologic role in protecting against environmental antigens and, due to their dendrite-like appearance and proximity to nerve endings, have been associated with the nervous system. This project aims to comprehensively understand the contribution of LCs to chronic itch, shedding light on a perplexing condition. LCs can be categorized into resident and monocyte-derived types. We hypothesize that resident LCs are implicated not only in acute itch but also in chronic itch. Aim 1 will examine the interaction of LCs with pruriceptors in mouse models of chronic itch. Utilizing transgenic mice expressing TdTomato in pruriceptors, we will visualize the localization of pruriceptors and LCs in chronic itch mouse models such as atopic dermatitis, psoriasis, and postburn. Optogenetic stimulation of LCs will be employed to determine if it activates pruriceptors. Aim 2 will evaluate the contribution of resident and/or monocyte-derived LCs to itch in mouse models of chronic itch. Utilizing hematopoietic chimeras with Gq- DREADD and Gi-DREADD expression, we will investigate the roles of resident and monocyte-derived LCs in spontaneous itch in chronic conditions. Chemogenetic activation and inhibition of these LC subsets will be explored to understand their influence on chronic itch. Aim 3 will identify and genetically define the heterogeneous population of resident and monocyte-derived LCs in mouse models of chronic itch. Single-cell RNA sequencing and cell sorting techniques will be employed to define the heterogeneous population of both LC types and examine how their dynamics change in mouse models of chronic itch. This comprehensive investigation seeks to unveil the overlooked role of LC-pruriceptor signaling in promoting spontaneous itch under diverse chronic conditions. The long-term goal of this study is to identify functional LC subsets, comprehend their impact on chronic itch, and pave the way for the development of more effective, mechanism- based treatments for this significant healthcare challenge.
