単一細胞および空間トランスクリプトミクスによる掌蹠膿疱症における骨髄-リンパ球クロストークと真皮免疫ニッチの解明

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 multi-omics approach.

We conducted single-cell RNA sequencing on pustular and non-pustular 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 Th17 cells from healthy control to non-pustular and pustular lesions. Cell-cell interaction analysis revealed CCL19-CCR7 interactions between fibroblastic reticular cell (FRC)-like fibroblasts and LAMP3+ migratory dendritic cells, and CCL22/CCL17-CCR4 interactions between dendritic cells and CD4 T cells, including Th17 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 PDE4 inhibitors as potential multi-target therapeutic candidates.

Collectively, our findings provide a comprehensive view of the immune dynamics in PPP and offer insights into effective treatment strategies.