Single‐cell and spatial transcriptomics reveal ACKR1+ endothelial cells associated with transcytosis in Leprosy

Abstract

Abstract Background Leprosy exhibits a dysregulated immune response, leading to excessive and inefficient inflammatory action. This can result in nerve damage, granuloma formation, and other clinical manifestations. Methods Single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomic analyses were applied to explore the intricate cellular landscape of leprosy, focusing on endothelial cells. The study encompasses a dataset of 36,517 cells obtained from normal skin, clinical form lepromatous leprosy (LL), and reversal reaction (RR). We applied advanced techniques, including pseudotime trajectory analysis, cell–cell interaction studies, and high-dimensional weighted gene co-expression network analysis (hdWGCNA). Results The profiling of cellular composition revealed significant disparities among leprosy types, emphasizing the role of specific cell types in each condition. CellChat and hdWGCNA analysis unveiled intricate intercellular interactions in the leprosy microenvironment, with a focus on the ACKR1 gene-mediated cytokine regulation in endothelial cells. Disease-associated endothelial cells highlighted a unique gene signature associated with vesicle-related processes, suggesting their involvement in vascular alterations in leprosy. Spatial transcriptome profiling in normal skin and leprosy sections provided insights into the heterogeneity of parenchyma cells, with distinct clusters observed in lepromatous leprosy. ACKR1 exhibited high expression in regions enriched with endothelial cells only in lepromatous leprosy, indicating a localized mechanism for cytokine regulation. Conclusions The central involvement of ACKR1 + endothelial cells in transcytosis and cytokine regulation provides potential avenues for therapeutic exploration. This study underscores the importance of advanced technologies in comprehending immune microenvironments for targeted interventions in leprosy and related infectious diseases.