Background and Aims: Perianal fistulizing Crohn's disease (PFCD) is a challenging complication with poorly understood pathogenesis and limited treatment options, largely due to the lack of clinically relevant animal models. Interferon-gamma (IFN-{gamma}) signaling is hyperactivated in human PFCD. We aimed to establish mouse models recapitulating human PFCD and to evaluate IFN-{gamma} as a new therapeutic target. Methods: Perianal fistulas were established in three mouse models with concurrent Crohn's disease-like intestinal inflammation: wild-type (WT) mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced proctocolitis, Il10-/- mice, and TNF{Delta}69AU/+ mice. A modified MAGNIFI-CD index was developed for longitudinal fistula assessment in mice. Transcriptomic analysis and flow cytometry were conducted on mouse fistula tissue. Re-analysis of single-cell and spatial transcriptomics of human PFCD tissues was performed. Therapeutic benefits of anti-TNF-, upadacitinib, and IFN-{gamma} pathway antagonists were evaluated in the PFCD models. Results: All three PFCD models sustained chronic perianal fistula tracts for at least 5 weeks after wire removal. All three models closely recapitulate the pathological and molecular features of PFCD in patients, as confirmed by clinical examination, MRI, histopathology, immunostaining, flow cytometry, and transcriptomics. IFN-{gamma} signaling emerged as a central and conserved pathway across all three mouse models and human PFCD. Targeting of the IFN-{gamma} pathway promptly improved fistula healing with mitigation of IFN-{gamma} signaling, inflammation, and epithelial-to-mesenchymal transition (EMT). Moreover, combining IFN-{gamma} and TNF- blockade demonstrated augmented therapeutic efficacy compared to anti-TNF- monotherapy. Conclusions: These PFCD mouse models and imaging tools provide first reliable and clinically relevant platforms for mechanistic studies and therapeutic evaluation. IFN-{gamma} signaling represents a potential therapeutic target warranting clinical investigation. Key words: perianal fistulizing Crohn's disease; preclinical models; interferon-gamma; epithelial-to-mesenchymal transition; therapeutic targeting
Yao, X., Ma, K., Ballard, D. H., Zhu, E., Liu, X., Huang, L., Tian, C., Quirk, J. D., Ruiz, H. S., Tan, T., Ciorba, M. A., Randolph, G., Deepak, P., Cao, S.
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