Single-cell and spatial transcriptomics unveil myeloid-lymphoid cross talk and the dermal immune niche underlying palmoplantar pustulosis.

Abstract

Palmoplantar pustulosis (PPP) is a chronic, recurrent inflammatory dermatosis characterized by sterile pustules on the palms and/or soles, and its pathogenesis remains incompletely understood. We sought to investigate the immune landscape underlying PPP progression using a multiomics approach. We conducted single-cell RNA sequencing on pustular and nonpustular sole lesions from patients with PPP. Key findings were further validated at the tissue level using high-resolution spatial transcriptomics (ST). We identified elevated JAK-STAT signaling in keratinocytes and fibroblasts, accompanied by a stepwise increase in myeloid dendritic cells and T_H17 cells from healthy control to nonpustular and pustular lesions. Cell-cell interaction analysis revealed CCL19-CCR7 interactions between fibroblastic reticular cell-like fibroblasts and LAMP3⁺ migratory dendritic cells, and CCL22/CCL17-CCR4 interactions between dendritic cells and CD4 T cells, including T_H17 populations. ST analysis confirmed these interactions in situ and identified a lymphoid-like immune niche within the CCL19⁺ upper dermis. Additionally, the pustule and surrounding keratinocytes were identified as major sources of CXCL1/6/8-ACKR1 signaling, facilitating neutrophil recruitment through interactions with endothelial cells. Together, these coordinated cell-cell interactions support an amplifying immune network that drives the formation of a spatially organized, dense immune niche during PPP progression. Finally, transcriptome-guided drug effect prediction identified JAK and phosphodiesterase-4 inhibitors as potential multitarget therapeutic candidates. Collectively, our findings provide a comprehensive view of the immune dynamics in PPP and offer insights into effective treatment strategies.