Single-cell landscape of immune remodeling in alopecia areata suggests MIF + fibroblasts and their potential ligand-receptor crosstalk with dendritic cells.

BACKGROUND

Alopecia areata (AA) is an autoimmune hair loss disorder. Although autoreactive CD8+ T cells are central effectors, the roles of stromal and epithelial compartments in sustaining inflammation remain unclear.

METHODS

This study analyzed publicly available scRNA-seq data from the GEO database (GSE212450, GSE233906), comprising 15 scalp samples from normal skin (NS), non-lesional (NL), and AA conditions. Following integration, normalization, and clustering, cells were annotated using established marker genes. Subclustering focused on immune, epithelial, and fibroblast lineages. Differential expression and enrichment analyses identified disease-associated genes and pathways. CellChat was used to compare ligand-receptor interactions and signaling networks between NS and AA microenvironments.

RESULTS

scRNA-seq analysis revealed a profoundly remodeled immune niche in AA lesions, extending beyond immune cells to encompass epithelial cells and fibroblasts. Key features included lymphoid-myeloid expansion, clonal cytotoxic CD8+ T1 cell accumulation, mast cell loss, and elevated DC3-derived IL-15. Epithelial cells exhibited upregulated MHC-II and immunomodulatory activity despite stable proportions. A novel pro-inflammatory fibroblast subset (FB3), enriched in AA, expressed high levels of MIF, displayed inflammatory and stress-related signatures, and suppressed extracellular matrix organization. Ligand-receptor analysis identified an intensified MIF-centered inflammatory circuit, primarily via MIF-(CD74 + CXCR4/CD44) axes, forming a robust signaling network connecting FB3 and multiple dendritic cell subsets.

CONCLUSION

This study reveals that fibroblasts in AA lesions, particularly the newly identified FB3 subset, are not merely passive structural cells but rather active participants in immune-inflammatory regulation through the elevated secretion of MIF. The enhanced MIF-(CD74 + CXCR4/CD44) signaling axis constitutes a core mechanism connecting FB3 cells with multiple dendritic cell subsets. This finding suggests that targeting FB3 differentiation or inhibiting MIF-related signaling pathways may represent a promising therapeutic avenue for AA.