Redefining airway wall immune–epithelial interactions using single-cell spatial transcriptomics

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Introduction: Asthma is among the most common immune-mediated diseases, affecting over 200 million people worldwide. Biologic therapies targeting type 2 inflammation are not universally effective, highlighting the need to better understand immune-stromal interactions within the airways. Spatial transcriptomics offers a unique opportunity to examine cellular organisation and crosstalk in intact tissue. Objectives: We wished to map the airway wall in health and asthma using single-cell spatial transcriptomics to identify distinct cellular neighbourhoods that may contribute to disease pathology. Methods: Endobronchial biopsies from healthy and asthmatic individuals were profiled using the 10X Xenium platform with a 339-gene panel targeting lung and immune pathways. Data were processed with the 10X pipeline, and clustering validated against the lung cell atlas. Spatial neighbourhoods were analysed using Seurat and CatsCradle. Results: We identified an aberrant epithelial neighbourhood enriched for a subset of ciliated cells that was present in asthma but absent in controls. These cells showed altered maturation, co-expressing ciliated (FOXJ1) and goblet (MUC1) markers, and were mislocalised between basal and luminal layers. Spatial ligand–receptor analysis revealed disrupted signalling, including increased extracellular matrix interactions and chemokine production consistent with a dysfunctional epithelial niche. Conclusion: Using spatial transcriptomics, we uncovered a unique set of cellular interactions with aberrant ciliated cells that contribute to impaired homeostasis and airway remodelling in asthma.

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