Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis

Feiyang Ma, Olesya Plazyo, Allison C. Billi, Lam C. Tsoi, Xianying Xing, Rachael Wasikowski, Mehrnaz Gharaee-Kermani, Grace Hile, Yanyun Jiang, Paul W. Harms, Enze Xing, Joseph Kirma, Jingyue Xi, Jer En Hsu, Mrinal K. Sarkar, Yutein Chung, Jeremy Di Domizio, Michel Gilliet, Nicole L. Ward, Emanual MaverakisEynav Klechevsky, John J. Voorhees, James T. Elder, Jun Hee Lee, J. Michelle Kahlenberg, Matteo Pellegrini, Robert L. Modlin, Johann E. Gudjonsson

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish
Article number3455
JournalNature communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

Fingerprint

Dive into the research topics of 'Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis'. Together they form a unique fingerprint.

Cite this