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Sekhon, Prabhreet

University of British Columbia

Crohn’s disease (CD) is one form of inflammatory bowel disease (IBD) in which inflammation penetrates all gut layers, and occurs discontinuously anywhere from the lips to the anus. One in 3 people with CD will develop a life-threatening complication called fibrosis. Fibrosis is driven by excessive deposition of extracellular matrix components and thickening of the bowel wall due to fibroblast activation and smooth muscle cell hyperplasia, respectively. There are currently no therapies to directly treat intestinal fibrosis, and surgery is the only available intervention. The Sly laboratory has previously characterized the src homology 2 (SH2) domain-containing inositol polyphosphate 5′-phosphatase deficient (SHIP-/-) mouse model of CD-like intestinal inflammation and fibrosis. They have shown a critical role of phosphatidylinositol 3-kinase (PI3K) p110δ-mediated upregulation of arginase I (ArgI) in intestinal fibrosis. ArgI is an enzyme that uses L-arginine to produce L-ornithine, which ultimately gets broken down into precursors used for collagen biosynthesis and cell proliferation. Previous studies have implicated a pro-fibrotic role of interleukin (IL)-33 by promoting ArgI expression in the context of lung fibrosis. Based on this, I hypothesized that IL-33 promotes fibrosis in the SHIP-/- model of CD by inducing ArgI activity. I found that IL-33 concentrations and relative gene expression were higher in the fibrotic sections of SHIP-/- mice compared to SHIP+/+ controls, specifically the 30 kDa isoform. IL-33 may synergize with IL-13 to induce ArgI expression and activity in SHIP-/- bone marrow derived macrophages (BMDMs). IL-33 neutralization and genetic ablation in vivo reduced mean ArgI activity in SHIP-/- non-fibrotic and fibrotic sections, however, did not improve disease. Because high IL-1β concentrations persisted upon IL-33 neutralization and genetic ablation in SHIP deficiency, I speculate that targeting both the pro- and anti-inflammatory responses are required to treat CD-associated fibrosis. Overall, these findings implicate an association between IL-33 and fibrosis in SHIP-/- mice, however, targeting IL-33 was insufficient to ameliorate intestinal fibrosis.

Text

2025-01-13

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90107

Women+ and Children’s Health Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/