Role of langerin+ cells in skin pathologies
Langerhans cells (LCs) are epidermal immune cells that express C-type lectin receptor langerin along with a subset of dermal dendritic cells. Langerin+ cells play a pivotal role in skin immunity. Previous research has suggested that LC may be involved in skin repair, but little is known about the importance of LC/ langerin+ cells or their specific role in wound healing processes. In this study the impact of ablation of langerin+ cells on healing of a full-thickness excision wound were investigated using the langerin-DTR LC-depletable mouse. Strikingly, depletion of langerin+ cells resulted in more rapid reduction in wound area. Accelerated wound healing in the langerin+ cell depleted group was characterized by enhanced neo-epidermis and granulation tissue formation, and increased cellular proliferation and angiogenesis within these newly formed tissues. The accelerated healing in the absence of langerin+ cells were associated with increased levels of GM-CSF and F4/80+ cells within the granulation tissue. RNA-seq analysis revealed that there was an increase in genes associated with muscle contraction and myofibril assembly pathways but a loss in genes associated with keratinization pathways was observed in the DT treated mice at day 0 post – wounding which could be contributing to the accelerated healing. Deconvolution of RNAseq data revealed that a potential increase in the percentage of eosinophils at D0 which was sustained throughout the healing process in the depleted group. An earlier infiltration of dendritic cells and M2 macrophages in the depleted group at earlier time points could be setting up the wound microenvironment more conducive for healing. Down regulation and delayed expression of genes in the complement cascade, neutrophil degranulation pathways support an inhibitory role for langerin+ cells during inflammatory phase of wound healing. Therapies that suppress langerin+ cells or their function may therefore have utility in progressing the healing of wounds in humans. Based on the inhibitory role of langerin+ cells on proliferation and angiogenesis in the wound, we predicted that in a highly proliferated and vascular condition such as a tumour, langerin+ cell numbers would decrease. However, in human squamous cell carcinoma tissues, we did not observe significant correlation between proliferation and angiogenesis in the tumour with langerin+ cells, tumour size of depth, indicating that the SCC microenvironment is not similar to the wounds. In contrast to our hypothesis, the distribution of langerin+ cells increased as the tumour size increased, suggesting that increased langerin+ cells might aid in tumorigenesis or the tumour microenvironment could be inhibiting the migration of langerin+ cells. Similar to the wounding experiments, GM-CSF and IL-17 exhibited opposing levels of expression in the centre and periphery of the tumour. Unlike in the wound healing tissues, langerin+ cells did not significantly correlate with other factors such as proliferation, angiogenesis, GM-CSF or IL-17, suggesting that langerin+ cells could be playing different roles according to the microenvironment. Further single cell sequencing in both mouse and human wounds and tumours would be highly beneficial to reduce the granularity of their roles in the varying skin microenvironment. Use of mouse models that ablate only the LCs or the langerin+ DCs can help elucidate their specific roles in the skin.
Advisor: Hibma, Merilyn; Wise, Lyn
Degree Name: Doctor of Philosophy
Degree Discipline: Department of Pathology
Publisher: University of Otago
Research Type: Thesis