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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299051 | GEO | 2026/03/09

REPOSITORIES: GEO

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Project description:Background. Generalized pustular psoriasis (GPP), palmoplantar pustular psoriasis (PPP) and Acrodermatitis continua suppurativa Hallopeau (ACH) are 3 prototypes of pustular psoriasis. Treating them with the established psoriasis armamentarium of immunomodulating therapies is more or less a trial-and-error game because pathophysiology has not been uncovered in detail yet. Objectives. To promote the decoding of immunological pathways in GPP as the maximal variant of pustular psoriasis. Methods. Focusing on transcriptomic differences in GPP versus PPP, bulk RNA sequencing of affected skin and healthy skin of 3 GPP and 3 PPP patients was performed, and results were compared to each other and to matching healthy skin samples. Results. Analysis of heatmaps confirmed the expected up-regulation of Interleukin (IL-) 17, IL-23 and IL-36 pathways, especially in GPP. Interestingly, in our GPP patients we detected an unexpected marked atopic-like milieu with an upregulated T-helper cell (Th) type 2 profile. This raises the bar concerning personalized medicine as recently introduced IL-36 blockage will probably not be able to succeed as a monotherapy in GPP. In PPP-patients the ‚typical‘ immune signatures, although differentially regulated, struck with a notable heterogeneity. The atopic markers were not as overregulated as in GPP. Further findings might elucidate clinical features of GPP: Severity of symptoms was accompanied by up-regulated SERPIN B4 and L-selectin. And, an overexpression of KYNU and TDO2 as a sign for imbalance in tryptophan metabolism could deliver an explanation for psychological findings like anxiety and depression during an acute flare of GPP. Conclusions. GPP has an atopic component next to notorious drivers of classical psoriasis and IL-36. Key factors for aggressiveness of disease and psychological distress during flares could be overexpression of SERPIN B4/L-selectin respectively KYNU/TDO2. Trials with a greater number of patients and even more meticulous transcriptome analysis possibly supported by artificial intelligence should be considered.

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

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