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. 2025 Jul 3;135(17):e193413.
doi: 10.1172/JCI193413. eCollection 2025 Sep 2.

Revealing hyperactivated IFN-γ pathways in perianal fistulizing Crohn's disease using single-cell and spatial multi-omics

Siyan Cao  1 , Khai M Nguyen  2 , Kaiming Ma  1 , Tingyi Tan  1 , Xin Yao  1 , Ta-Chiang Liu  2 , Malek Ayoub  1 , Jalpa Devi  1 , Sami Samaan  1 , Yizhou Liu  2 , Radhika Smith  3 , Matthew L Silviera  3 , Steven R Hunt  3 , Paul E Wise  3 , Matthew G Mutch  3 , Sean C Glasgow  3 , William C Chapman Jr  3 , Michelle L Cowan  3 , Matthew A Ciorba  1 , Marco Colonna  2 , Parakkal Deepak  1 ; SPARC IBD Investigators
Collaborators, Affiliations

Revealing hyperactivated IFN-γ pathways in perianal fistulizing Crohn's disease using single-cell and spatial multi-omics

Siyan Cao et al. J Clin Invest. .

Abstract

Up to 40% patients with Crohn's disease suffer from perianal disease, a debilitating complication with unclear etiology. This study identified unique pathophysiology which may help develop novel therapies.

Keywords: Cellular immune response; Gastroenterology; Immunology; Inflammatory bowel disease; Therapeutics.

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Conflict of interest statement

Conflict of interest: The conflict-of-interest statement is available in the Supplemental Material.

Figures

Figure 1
Figure 1. Hyperactivated IFN-γ signaling is a distinguishing feature of PCD in both fistula tracts and intestinal mucosa.
(A) UMAP of major cell compartments in perianal fistulas. (B) Top upregulated pathways in PCD versus IPF fistulas by SCPA. (C) Altered gene expression in monocytes, macrophages, and dendritic cells in PCD versus IPF fistulas. (D) Representative IHC images and quantification in fistula tracts. Scale bar: 50 μm. **P < 0.01. (E) Top upregulated pathways in rectum (PCD vs. PCD healed) and colon/terminal ileum (PCD vs. NPCD) by SCPA. (F) UMAP of rectal epithelial cells; single-cell module scores; and correlation between TNF or IFNG response and EMT scores. (G) IFN-γ senders in PCD and IPF. (H) IFN-γ downstream genes in bulk RNA-Seq of CD intestinal samples. P values generated by Dunn’s post hoc test: STAT1, 0.019 (active vs. no PCD); IRF1, 0.00024 (active vs. no PCD) and 0.012 (inactive vs. no PCD); IRF8, 0.014 (active vs. no PCD).
See this image and copyright information in PMC

References

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