- Ma, Feiyang;
- Plazyo, Olesya;
- Billi, Allison C;
- Tsoi, Lam C;
- Xing, Xianying;
- Wasikowski, Rachael;
- Gharaee-Kermani, Mehrnaz;
- Hile, Grace;
- Jiang, Yanyun;
- Harms, Paul W;
- Xing, Enze;
- Kirma, Joseph;
- Xi, Jingyue;
- Hsu, Jer-En;
- Sarkar, Mrinal K;
- Chung, Yutein;
- Di Domizio, Jeremy;
- Gilliet, Michel;
- Ward, Nicole L;
- Maverakis, Emanual;
- Klechevsky, Eynav;
- Voorhees, John J;
- Elder, James T;
- Lee, Jun Hee;
- Kahlenberg, J Michelle;
- Pellegrini, Matteo;
- Modlin, Robert L;
- Gudjonsson, Johann E
The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2+ fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2+ fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2+ myeloid cells, CCR7+ LAMP3+ dendritic cells, and CXCR4 expressed on both CD8+ Tc17 cells and keratinocytes, respectively. The SFRP2+ fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.