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Deficiency in macrophage-stimulating protein results in spontaneous intestinal inflammation and increased
Merlijn Witte1, Leonie F A Huitema, Edward E S Nieuwenhuis
11 Laboratory for Translational Immunology, Wilhelmina Children's Hospital Utrecht, University Medical Centre Utrecht , Utrecht, the Netherlands .
Abstract:
Several genome-wide association studies have identified the genes encoding for macrophage-stimulating protein (MSP) and its receptor RON (Recepteur d'Origine Nantais) as possible susceptibility factors in inflammatory bowel disease. While it has been shown that the MSP-RON signaling pathway is involved in tissue injury responses, current mouse models for MSP and RON deficiency have not clearly demonstrated a role of MSP-RON signaling in the context of intestinal inflammation. In this study, we report that the recently identified zebrafish Msp mutant (msp(t34230)) develops spontaneous intestinal inflammation over time. From 14 to 28 weeks postfertilization Msp-deficient zebrafish show intestinal eosinophilia, increased intestinal expression of inflammatory marker mmp9, and activation of intestinal goblet cells. Moreover, these Msp mutant zebrafish are more susceptible toward ethanol-induced epithelial damage, which resulted in increased infiltration and proliferation of immune cells within the lamina propria and prolonged intestinal proinflammatory cytokine responses in some mutant fish. In light of the recent development of many tools to visualize, monitor, and genetically modify zebrafish, these Msp-deficient zebrafish will enable in-depth in vivo analysis of epithelial and macrophage-specific MSP-RON signaling in the context of intestinal inflammation.
Insights
Macrophage-stimulating protein (MSP) deficiency in zebrafish causes spontaneous intestinal inflammation, including eosinophilia and increased inflammatory markers. This finding highlights MSP-RON signaling
Area of Science:
- Immunology
- Gastroenterology
- Zebrafish models
Background:
- Genome-wide association studies suggest macrophage-stimulating protein (MSP) and its receptor RON (Recepteur d'Origine Nantais) are linked to inflammatory bowel disease susceptibility.
- The MSP-RON signaling pathway is implicated in tissue injury, but its role in intestinal inflammation remains unclear in existing mouse models.
Purpose of the Study:
- To investigate the role of MSP-RON signaling in intestinal inflammation using a zebrafish model.
- To characterize the phenotype of Msp-deficient zebrafish regarding intestinal inflammation.
Main Methods:
- Utilized a newly identified zebrafish Msp mutant (msp(t34230)).
- Monitored spontaneous intestinal inflammation from 14 to 28 weeks postfertilization.
- Assessed intestinal eosinophilia, mmp9 expression, goblet cell activation, and response to ethanol-induced epithelial damage.
Main Results:
- Msp-deficient zebrafish exhibited spontaneous intestinal inflammation, including eosinophilia and increased mmp9 expression.
- Mutant fish showed goblet cell activation and heightened susceptibility to ethanol-induced epithelial damage.
- Ethanol challenge led to increased immune cell infiltration, proliferation, and prolonged proinflammatory cytokine responses in Msp mutant zebrafish.
Conclusions:
- Msp-deficient zebrafish serve as a valuable in vivo model for studying MSP-RON signaling in intestinal inflammation.
- This model facilitates further investigation into epithelial and macrophage-specific roles of MSP-RON signaling.
- The findings underscore the potential involvement of the MSP-RON pathway in the pathogenesis of intestinal inflammatory conditions.
