Enhanced Translational Activity Is Linked to Lymphatic Endothelial Cell Activation in Cutaneous Leishmaniasis

Abstract

Introduction: Cutaneous leishmaniasis (CL) is a significant public health problem leading to permanently disfiguring skin lesions caused by Leishmania parasites. Lesion severity stems from an excessive host inflammatory response that prevents healing. Materials and Methods: Here, we characterized the transcriptional and translational responses of lymphatic endothelial cells (LECs) during murine CL using single-cell RNA sequencing data combined with flow cytometry and in vivo puromycin incorporation to assess translational activity. Results: We identified upregulation of antigen presentation pathways including MHC-I, MHC-II, and immunoproteasome transcripts in dermal LECs from Leishmania major-infected mice compared to naive controls. LECs also exhibited increased expression of guanylate binding proteins and interferon-inducible genes, indicative of immune activation. Moreover, our findings demonstrate that LECs in leishmanial lesions displayed heightened translational activity relative to LECs from uninflamed ears, and LEC translational activity was highest in activated LECs. Furthermore, LEC translational activity exceeded that of other cell types within the lesion microenvironment. Validating the transcriptomic data, LECs in lesions expressed elevated MHC-II and programmed death-ligand 1 (PDL-1), supporting their potential role in antigen presentation. Functional assays using DQ-ovalbumin confirmed that LECs from leishmanial lesions efficiently uptake and process antigens, highlighting their capability as antigen presenting cells in the inflamed dermal microenvironment. Conclusion: Overall, our study reveals the activation status of LECs in leishmanial lesions, shedding light on their potential role in shaping local immunity and inflammation in a variety of skin diseases.