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Updated: Dec 14, 2025
Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin
Published on: September 12, 2019
AXL Is a Potential Target for the Treatment of Intestinal Fibrosis
Calen A Steiner1, Eva S Rodansky1, Laura A Johnson1
1Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Background:
Fibrosis is the final common pathway to intestinal failure in Crohn's disease, but no medical therapies exist to treat intestinal fibrosis. Activated myofibroblasts are key effector cells of fibrosis in multiple organ systems, including the intestine. AXL is a receptor tyrosine kinase that has been implicated in fibrogenic pathways involving myofibroblast activation. We aimed to investigate the AXL pathway as a potential target for the treatment of intestinal fibrosis.
Methods:
To establish proof of concept, we first analyzed AXL gene expression in 2 in vivo models of intestinal fibrosis and 3 in vitro models of intestinal fibrosis. We then tested whether pharmacological inhibition of AXL signaling could reduce fibrogenesis in 3 in vitro models of intestinal fibrosis. In vitro testing included 2 distinct cell culture models of intestinal fibrosis (matrix stiffness and TGF-β1 treatment) and a human intestinal organoid model using TGF-β1 cytokine stimulation.
Results:
Our findings suggest that the AXL pathway is induced in models of intestinal fibrosis. We demonstrate that inhibition of AXL signaling with the small molecule inhibitor BGB324 abrogates both matrix-stiffness and transforming growth factor beta (TGF-β1)-induced fibrogenesis in human colonic myofibroblasts. AXL inhibition with BGB324 sensitizes myofibroblasts to apoptosis. Finally, AXL inhibition with BGB324 blocks TGF-β1-induced fibrogenic gene and protein expression in human intestinal organoids.
Conclusions:
The AXL pathway is active in multiple models of intestinal fibrosis. In vitro experiments suggest that inhibiting AXL signaling could represent a novel approach to antifibrotic therapy for intestinal fibrosis such as in Crohn's disease.
Insights
Targeting the AXL pathway with BGB324 shows promise for treating intestinal fibrosis. This approach inhibits myofibroblast activation and promotes apoptosis, offering a potential new therapy for conditions like Crohn
Area of Science:
- Gastroenterology
- Molecular Biology
- Drug Discovery
Background:
- Intestinal fibrosis is a major complication of Crohn's disease, leading to intestinal failure.
- Currently, no effective medical therapies exist to treat intestinal fibrosis.
- Activated myofibroblasts are central to fibrosis, and the AXL receptor tyrosine kinase pathway is implicated in their activation.
Purpose of the Study:
- To investigate the AXL pathway as a potential therapeutic target for intestinal fibrosis.
- To determine if pharmacological inhibition of AXL signaling can reduce fibrogenesis in intestinal fibrosis models.
Main Methods:
- AXL gene expression was analyzed in vivo and in vitro models of intestinal fibrosis.
- Pharmacological inhibition of AXL signaling was tested using the small molecule inhibitor BGB324.
- In vitro models included matrix stiffness, TGF-β1 treatment in colonic myofibroblasts, and human intestinal organoids.
Main Results:
- The AXL pathway is upregulated in various models of intestinal fibrosis.
- BGB324 inhibited both matrix stiffness- and TGF-β1-induced fibrogenesis in human colonic myofibroblasts.
- AXL inhibition with BGB324 sensitized myofibroblasts to apoptosis and blocked TGF-β1-induced fibrogenic gene expression.
Conclusions:
- The AXL pathway is demonstrably active in intestinal fibrosis.
- Inhibiting AXL signaling presents a novel therapeutic strategy for antifibrotic treatment in intestinal fibrosis, including Crohn's disease.
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