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 Domizio, Michel Gilliet, Nicole L. Ward, Emanual Maverakis, Eynav Klechevsky, John J. Voorhees, James T. Elder, Jun Hee Lee, J. Michelle Kahlenberg, Matteo Pellegrini, Robert L. Modlin and Johann E. Gudjonsson ()
Additional contact information
Feiyang Ma: University of Michigan
Olesya Plazyo: University of Michigan
Allison C. Billi: University of Michigan
Lam C. Tsoi: University of Michigan
Xianying Xing: University of Michigan
Rachael Wasikowski: University of Michigan
Mehrnaz Gharaee-Kermani: University of Michigan
Grace Hile: University of Michigan
Yanyun Jiang: University of Michigan
Paul W. Harms: University of Michigan
Enze Xing: University of Michigan
Joseph Kirma: University of Michigan
Jingyue Xi: University of Michigan Medical School
Jer-En Hsu: University of Michigan Medical School
Mrinal K. Sarkar: University of Michigan
Yutein Chung: University of Michigan
Jeremy Domizio: University Hospital of Lausanne
Michel Gilliet: University Hospital of Lausanne
Nicole L. Ward: Case Western Reserve University
Emanual Maverakis: University of California Davis
Eynav Klechevsky: Washington University School of Medicine
John J. Voorhees: University of Michigan
James T. Elder: University of Michigan
Jun Hee Lee: University of Michigan Medical School
J. Michelle Kahlenberg: University of Michigan
Matteo Pellegrini: University of California
Robert L. Modlin: University of California
Johann E. Gudjonsson: University of Michigan

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39020-4

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DOI: 10.1038/s41467-023-39020-4

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