Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa
Kelsey R. van Straalen, … , Lam C. Tsoi, Johann E. Gudjonsson
Kelsey R. van Straalen, … , Lam C. Tsoi, Johann E. Gudjonsson
Published December 5, 2023
Citation Information: J Clin Invest. 2024;134(3):e169225. https://doi.org/10.1172/JCI169225.
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Research Article Dermatology Inflammation

Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa

Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications.

Authors

Kelsey R. van Straalen, Feiyang Ma, Pei-Suen Tsou, Olesya Plazyo, Mehrnaz Gharaee-Kermani, Marta Calbet, Xianying Xing, Mrinal K. Sarkar, Ranjitha Uppala, Paul W. Harms, Rachael Wasikowski, Lina Nahlawi, Mio Nakamura, Milad Eshaq, Cong Wang, Craig Dobry, Jeffrey H. Kozlow, Jill Cherry-Bukowiec, William D. Brodie, Kerstin Wolk, Özge Uluçkan, Megan N. Mattichak, Matteo Pellegrini, Robert L. Modlin, Emanual Maverakis, Robert Sabat, J. Michelle Kahlenberg, Allison C. Billi, Lam C. Tsoi, Johann E. Gudjonsson

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Figure 2

Ligand-receptor interactions between cell types.

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Ligand-receptor interactions between cell types. (A) Heatmap showing the...
(A) Heatmap showing the number of ligand-receptor pairs with a higher score in HS compared with NS among the cell types. Rows, cell type expressing ligand; columns, cell type expressing receptor. ML, myeloid cells; FB, fibroblasts; EC, endothelial cells; KC, keratinocytes; SMC, smooth muscle cells; MLNC, melanocytes; TC, T cells; Mast, mast cells; PLC, plasma cells; BC, B cells. (B–E) Circos plots showing cytokine and growth factor ligand-receptor interactions with higher scores in HS compared with NS in which ligands are expressed by myeloid cells (B), keratinocytes (C), FBs (D), and endothelial cells (E) with receptors expressed by other cell types.