Single-cell and spatial transcriptome profiling reveals innate-adaptive crosstalk in alopecia areata 2251484
TL;DR
Findings support that macrophages play a pivotal role in driving local immune dysregulation in AA and targeting macrophage subsets may represent a promising therapeutic approach for restoring HF immune privilege and ameliorating disease progression.
Abstract
Alopecia areata (AA) is an autoimmune disorder characterized by immune-mediated attack on hair follicles, resulting in non-scarring hair loss. The collapse of hair follicle (HF) immune privilege (IP) is widely regarded as a central pathogenic mechanism in AA. While CD8+ T cells have been extensively studied in this context, the contribution of macrophages to disease initiation and progression remains less defined. In this study, we investigated the roles of macrophages and CD8+ T cells in shaping immune cell recruitment and local immune dysregulation in AA lesions. Using single-cell transcriptomics, flow cytometry, and immunofluorescence during the development of an AA mouse model, we observed robust expansion and transcriptional reprogramming of CD8+ T cells, accompanied by prominent macrophage infiltration surrounding affected HFs. Interrogation of macrophage populations identified two transcriptionally distinct subpopulations: Folr2+ tissue-resident macrophages (TRMacs) and Folr2⁻ monocyte-derived macrophages (MoMacs). Each subset displayed unique gene-expression profiles enriched for pathways involved in T cell activation, leukocyte trafficking, and myeloid differentiation. Integration of spatial transcriptomic and flow cytometry imaging analyses revealed close spatial interactions between macrophage subsets and CD8+ T cells, with macrophage abundance positively correlating with CD8+ T cell infiltration. To assess functional relevance, we depleted macrophages with an antibody directed against colony-stimulating factor 1 receptor (CSF1R) in AA-grafted mice. Macrophage ablation markedly reduced both hair loss severity and the accumulation of cytotoxic NKG2D+ CD8+ T cells in lesional skin. Together, these findings support that macrophages play a pivotal role in driving local immune dysregulation in AA. Targeting macrophage subsets may represent a promising therapeutic approach for restoring HF immune privilege and ameliorating disease progression. n/a Basic Autoimmunity (BA)