Immune Dynamics in Palmoplantar Pustulosis Unveiled by Single-Cell and High-Resolution Spatial Transcriptomics [scRNA-seq]

Palmoplantar pustulosis (PPP) is a chronic and relapsing inflammatory skin disorder marked by the appearance of sterile pustules on the palms and/or soles, with an underlying pathogenesis that remains only partially understood. In this study, we mapped the immune landscape underlying PPP progression using single-cell RNA sequencing (scRNA-seq) integrated with high-resolution spatial transcriptomics (ST). Keratinocytes and fibroblasts in PPP showed enhanced activation of the JAK–STAT signaling pathway, alongside a progressive accumulation of myeloid dendritic cells and Th17 cells across disease stages—from healthy control (HC) to non-pustular lesion (NPL), and then to pustular lesion (PL). Cell–cell interaction analysis revealed CCL19–CCR7 signaling between fibroblastic reticular cell (FRC)-like fibroblasts and LAMP3⁺/CCR7⁺ migratory dendritic cells, as well as CCL22/CCL17–CCR4 signaling between these dendritic cells and CD4⁺ T cells, including Th17 subsets. These interactions were spatially validated, with dendritic cells localized both within pustules and in the upper dermis. Within the CCL19⁺ dermal compartment, activated antigen-presenting cells and lymphocytes coalesced into a lymphoid-like immune structure. Moreover, pustular and surrounding keratinocytes emerged as key sources of CXCL1/6/8–ACKR1 signaling, promoting neutrophil infiltration via endothelial engagement. These coordinated cellular interactions contribute to the establishment of a spatially organized and densely populated immune niche during PPP progression. Lastly, transcriptome-based drug prediction analysis highlighted JAK inhibitors and phosphodiesterase-4 (PDE4) inhibitors as promising therapeutic candidates capable of targeting multiple components of PPP pathology. Overall, this work provides an integrative view of immune dynamics in PPP and offers potential avenues for more targeted and effective therapies.