# Single‐Cell Transcriptomic Analysis Reveals an Inflammatory Antigen‐Presenting Macrophages Subtype Drive Vitiligo Pathogenesis Through STAT1‐Mediated Dual Mechanisms

## TL;DR

This study identifies a specific type of inflammatory macrophage that contributes to vitiligo by inhibiting melanocytes and activating T-cells, with STAT1 as a key target for treatment.

## Contribution

The discovery of an inflammatory antigen-presenting macrophage subtype and its dual role in vitiligo pathogenesis through STAT1-mediated mechanisms.

## Key findings

- Inflammatory antigen-presenting macrophages (Mac-InflamAP) are significantly enriched in vitiligo lesions and promote melanocyte loss.
- STAT1 is a key regulator in Mac-InflamAP and its inhibition reduces T-cell activation and macrophage M1-polarization.
- Fludarabine, a STAT1 inhibitor, ameliorates vitiligo progression in vivo.

## Abstract

Vitiligo is a common depigmentary disorder characterized by progressive melanocyte (MEL) loss. While T‐cell activation is central to its pathogenesis, the role of macrophages remains poorly understood. This study characterizes macrophage heterogeneity and function in vitiligo using single‐cell transcriptomic analysis and experimental validation.

We analyzed single‐cell RNA sequencing (scRNA‐seq) data from healthy and vitiligo‐affected skin to identify macrophage subpopulations. Computational analyses included cell subpopulation clustering, pseudotime trajectory inference, cell–cell communication, and high‐dimensional weighted gene coexpression network analysis (hdWGCNA). In vivo and in vitro experiments examined the effects of STAT1 suppression on the macrophage inflammatory phenotype and antigen presentation capacity.

scRNA‐seq analysis identified macrophages and T cell subsets enriched in vitiligo. Macrophage subclustering identified five subpopulations, with inflammatory antigen‐presenting macrophages (Mac‐InflamAP) significantly enriched in vitiligo lesions and M1‐polarized. Pseudotime analysis revealed Mac‐InflamAP as a terminal differentiation state. Cell–cell communication analysis showed Mac‐InflamAP exerts TNF‐mediated inhibitory effects on MELs while enhancing T‐cell antigen presentation, thereby promoting MEL loss. hdWGCNA identified STAT1 as a key regulator highly expressed in Mac‐InflamAP. In vivo, STAT1 inhibition by fludarabine ameliorated vitiligo progression by suppressing T cell activation and macrophage M1‐polarization. In vitro experiments confirmed STAT1 suppression reduced macrophage M1 polarization, inflammatory phenotype, and antigen presentation capabilities.

This study reveals an uncharacterized inflammatory macrophage subpopulation crucial to vitiligo pathogenesis through dual mechanisms: direct MEL inhibition and enhanced T‐cell activation. The identification of STAT1 as a key regulatory molecule provides a novel therapeutic target for vitiligo. These findings advance our understanding of immune‐mediated mechanisms in vitiligo.