Cell atlas of palmoplantar pustulosis reveals inflammation-associated fibroblast populations

Summary: Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterized by recurrent sterile pustules on the palms and soles. However, the role of fibroblasts in the disease pathogenesis remains unclear. To investigate the cellular heterogeneity and microenvironmental alterations in PPP, we performed single-cell RNA sequencing on paired lesional and non-lesional skin samples from a PPP patient. Through unbiased clustering analysis, we identified eight major cell populations, including keratinocytes, T cells, antigen-presenting cells, endothelial cells and fibroblasts, among others. Our study revealed novel fibroblast subpopulations with distinct inflammatory signatures. Specifically, we identified six FIB subsets characterized by the expression of unique marker genes, including CCL19, CCL26, COMP, CXCL12, IGFBP7, and TIMP3. Comparative analysis between lesional and non-lesional areas revealed a significant expansion of five FIB subsets in the lesional skin, suggesting their potential role in PPP pathogenesis. Notably, the COMP fibroblast subset was the only group that showed a marked decrease in lesional areas, whereas all other subsets were significantly upregulated in inflamed regions. This pattern highlights a dynamic shift in fibroblast composition, indicating that different FIB subsets may contribute to disease progression through distinct mechanisms. The enrichment of inflammatory-associated fibroblasts in PPP lesions suggests their involvement in immune cell recruitment, extracellular matrix remodeling, and tissue inflammation. Our findings provide novel insights into fibroblast heterogeneity in PPP and suggest that fibroblast subsets actively participate in shaping the inflammatory microenvironment. Targeting specific fibroblast populations may offer new therapeutic opportunities for treating PPP. Further research is needed to explore the molecular pathways regulating these fibroblast subsets and their crosstalk with immune cells. Yuxin Zheng¹, Xi-Bei Chen¹, Xiao-Yong Man¹ 1. Dermatology, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, China. Cell Communication Networks and Stromal Biology