Abstract Background Inflammatory bowel diseases (IBD) are frequently complicated by intestinal fibrosis and strictures formation, occurring in more than 50% of Crohn’s disease and 5% of ulcerative colitis. Intestinal fibrosis leads to surgery and strictures frequently recur leading to repeated surgeries1. There is currently no specific therapy to prevent or inhibit intestinal fibrosis and this therefore constitutes a major treatment challenge. Intestinal fibrosis is characterized by excessive deposition of extracellular matrix (ECM) synthesized by intestinal myofibroblasts1. Interleukin-33 (IL-33) is a pleiotropic nuclear cytokine involved in immunoregulation and tissue repair2. Following cellular injury IL-33 is released by epithelial and endothelial cells as well as fibroblast. Binding to ST2 (suppressor of tumorigenicity 2) receptor, IL-33 induces nuclear translocation of transcription factor NF-κB, thus promoting inflammation2. Additionally, IBD patients have increased colonic expression of IL-33 and ST2 in epithelial cells compared to healthy controls3. The inflammatory role of IL-33 has been defined, but its role in intestinal fibrosis remains to be elucidated. We hypothesized that IL-33 may be involved in IBD-associated intestinal fibrosis. We therefore aimed to characterize IL-33/ST2 signaling pathway in IBD-patients, activated fibroblast cell line (CCD-18 Co) and a colitis mice model. Methods IL33 (IL-33) and IL1RL1 (ST2) mRNA expression have been assessed in (i) RNAseq data performed on IBD patients-isolated colonic biopsies (EGAS00001002702)4, (ii) TGF-β-activated human colonic fibroblasts (CCD-18 Co; TGF-β, 10 ng/mL) and (iii) colonic biopsies from dextran sulfate sodium (DSS)-induced chronic colitis model (DSS 1%). Fibrotic markers were measured in DSS model and CCD-18 Co. Results IL33 and IL1RL1 mRNA levels are increased in inflammatory colon biopsies from IBD-patients compared to healthy and non-inflammatory IBD-patients (****p 0.0001) (Figure 1A-B). TGF-β decreased IL33 mRNA levels in CCD-18 Co (**p 0.01) (Figure 1C) and induced no effect for IL1RL1 expression (Figure 1D). DSS decreased Il33 mRNA levels (**p 0.01) and increased Il1rl1 mRNA levels (**p 0.01) (Figure 1E) associated with increase of Col1a1 mRNA levels (r = 0,8904, *p 0.05) (Figure 1F). Conclusion While IL33 mRNA levels are increased in inflammatory conditions in colon IBD biopsies, it is not the case in experimental models of intestinal fibrosis. However, higher levels of its receptor IL1RL1 are observed in human IBD patients and in vivo model of intestinal fibrosis. As cellular heterogeneity is involved in intestinal fibrosis, it would be interesting to study the activation of signaling pathways involving IL-33 and ST2 in the development of intestinal fibrosis. References: 1. Amamou A, Leboutte M, Breton J, and al. Mineralocorticoid receptor activation contributes to intestinal fibrosis through neutrophil gelatinase-associated lipocalin in preclinical models. Nat Commun. 2025;16(1):6318. doi:10.1038/s41467-025-61401-0 2. England E, Rees DG, Scott IC, and al. Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction. Sci Rep. 2023;13(1):9825. doi:10.1038/s41598-023-36642-y 3. Beltrán CJ, Núñez LE, Díaz-Jiménez D, and al. Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2010;16(7):1097-1107. doi:10.1002/ibd.21175 4. Hu S, Bourgonje AR, Gacesa R, and al. Mucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease. Nat Commun. 2024;15(1):1470. doi:10.1038/s41467-024-45855-2 Conflict of interest: Ms. Ratel, Lise: No conflict of interest Rebollo, Elise: No conflict of interest Hermoso, Marcela: No conflict of interest Savoye, Guillaume: No conflict of interest Leboutte, Mathilde: No conflict of interest Marion-Letellier, Rachel: No conflict of interest
Ratel et al. (Thu,) studied this question.