Citation Information: JCI Insight. 2025;10(18):e193038. https://doi.org/10.1172/jci.insight.193038.
Abstract
Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disorder marked by erythematous pustules and desquamation on the palms and soles. While IL-17 pathways are implicated in PPP, IL-17 blockers have shown modest efficacy, underscoring the need for a deeper understanding of IL-17 involvement. To dissect the cellular and spatial architecture of PPP, we performed single-cell RNA-Seq (scRNA-Seq) on lesional, nonlesional, and healthy acral skin to examine cellular composition, transcriptomic profiles, and cell-cell interactions. Unbiased clustering revealed 9 major cell types, including an inflammatory keratinocyte subset enriched in IL-17A/TNF signatures and marked by high IL-36G expression. Within the lymphocyte compartment, we identified a hybrid “regTh17” population coexpressing regulatory markers (FOXP3, CTLA4, TIGIT), IL17F, and IL26. This regTh17 subset was distinguished by elevated IL1R1 and CD39, suggesting an IL-1β–driven differentiation. Spatial analyses demonstrated significant neighborhood enrichment of regTh17 cells with IL-36G+ supraspinous keratinocytes. RegTh17 cells were the predominant source of IL-17F and IL-26 signals, whereas keratinocytes were predicted as their main receivers. We further observed regTh17 coexpressing TNFRSF4 (OX40) and TNFRSF18 (GITR) specifically at sites of IL36G+ keratinocyte interactions, implicating these pathways in amplification of the IL-17/IL-36 inflammatory loop. Together, our integrated single-cell and spatial profiling uncovers Th17 plasticity in PPP, identifies a regTh17-keratinocyte interaction, and highlights IL-17F, IL-26, OX40/OX40L, and GITR/GITRL as candidate targets for precision therapies in this challenging disease.
Authors
Tran H. Do, Rachael Bogle, Haihan Zhang, Xianying Xing, Mehrnaz Gharaee-Kermani, Madalina Raducu, Jennifer Fox, Rundong Jiang, Olesya Plazyo, Paul W. Harms, Mio Nakamura, Enze Xing, Michel Gilliet, Allison C. Billi, J. Michelle Kahlenberg, Robert L. Modlin, Ozge Uluckan, Lam C. Tsoi, Johann E. Gudjonsson
