title: Deficiency in macrophage-stimulating protein results in spontaneous intestinal inflammation and increased susceptibility toward epithelial damage in zebrafish.
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.
authors.affiliation: 1 Laboratory for Translational Immunology, Wilhelmina Children's Hospital Utrecht, University Medical Centre Utrecht , Utrecht, the Netherlands .
authors.forename: Merlijn
authors.initials: M
authors.lastname: Witte
authors.forename: Leonie F A
authors.initials: LF
authors.lastname: Huitema
authors.forename: Edward E S
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.forename: Sylvia
authors.initials: S
authors.lastname: Brugman
mesh_terms: D000818:Animals; D016207:Cytokines; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D020397:Goblet Cells / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000172:deficiency* / Q000235:genetics; D006652:Histological Techniques; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics* / Q000473:pathology*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D018709:Statistics, Nonparametric; D015027:Zebrafish
chemical_list: D016207:Cytokines; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D020780:Matrix Metalloproteinase 9