Mast cell–derived IL-13 as a driver of Crohn disease–associated intestinal fibrosis

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ID: 319956
2026
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Abstract
Abstract Background Crohn disease is a chronic, immune-mediated disease that can lead to intestinal fibrosis, strictures, and bowel obstruction. The Src homology 2 domain-containing inositol polyphosphate 5′-phosphatase-deficient (SHIP−/−) mouse develops spontaneous Crohn disease–like ileal inflammation and fibrosis. Fibrosis depends on increased phosphatidylinositol 3-kinase p110δ activity downstream of interleukin 4 (IL-4) or IL-13. Because current anti-inflammatory treatments do not prevent or reverse fibrosis, we aimed to identify the key cytokine(s) and its cellular source(s). Methods We blocked IL-4 or IL-13 in mice by use of neutralizing antibodies or genetic ablation. Intestinal inflammation and fibrosis were assessed by gross pathology, histopathology, collagen accumulation, muscle thickening, immune cell infiltration, and tissue IL-1β concentrations. IL13 and its cellular source in stricturing Crohn disease were examined using single-cell RNA sequencing and RNAscope. Mast cells and Il13 were also assessed in ileal cross-sections from SHIP+/+ and SHIP−/− mice. Results Blocking or genetic ablation of IL-13, but not IL-4, significantly reduced ileal fibrosis in mice, including collagen accumulation, smooth muscle thickening, vimentin + cells, and proliferating vimentin + cells. Blockade of IL-13 also reduced intestinal inflammation, including immune cell infiltration and ileal IL-1β concentrations. Single-cell RNA-sequencing analyses identified mast cells as the exclusive source of IL13 in stricturing Crohn disease. Human resection tissues confirmed increased mast cells in diseased small intestine and identified mast cells as the source of IL13. SHIP−/− mice similarly showed increased ileal mast cells that were also a source of IL13. Conclusions IL-13 is critical for intestinal fibrosis in SHIP-deficient mice, and mast cells are a source of IL13 in Crohn disease–associated intestinal fibrosis.
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Authors Kwestan Safari, Wei Jen, Prabhreet Sekhon, Priya Rai, Susan C. Menzies, Tomoaki Hoshino, Anne-Sophie Fratzscher, Andrew Roth, Karen Madsen, Laura M. Sly
Journal inflammatory bowel diseases
Year 2026
DOI
10.1093/ibd/izag127
URL
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