Matrix metalloproteinases (MMPs) are potential biomarkers for disease activity in inflammatory bowel disease (IBD). However, clinical trials targeting MMPs have not succeeded, likely due to poor understanding of the biological functions of individual MMPs. Here, we explore the role of MMP-19 in IBD pathology. Using a DSS-induced model of colitis, we show evidence for increased susceptibility of Mmp-19-deficient (Mmp-19(-/-)) mice to colitis. Absence of MMP-19 leads to significant disease progression, with reduced survival rates, severe tissue destruction, and elevated levels of pro-inflammatory modulators in the colon and plasma, and failure to resolve inflammation. There was a striking delay in neutrophil infiltration into the colon of Mmp-19(-/-) mice during the acute colitis, leading to persistent inflammation and poor recovery; this was rescued by reconstitution of irradiated Mmp-19(-/-) mice with wild-type bone marrow. Additionally, Mmp-19-deficient macrophages exhibited decreased migration in vivo and in vitro and the mucosal barrier appeared compromised. Finally, chemokine fractalkine (CX3CL1) was identified as a novel substrate of MMP-19, suggesting a link between insufficient processing of CX3CL1 and cell recruitment in the Mmp-19(-/-) mice. MMP-19 proves to be a critical factor in balanced host response to colonic pathogens, and for orchestrating appropriate innate immune response in colitis.
- MeSH
- chemokin CX3CL1 metabolismus MeSH
- cytokiny metabolismus MeSH
- idiopatické střevní záněty imunologie MeSH
- infiltrace neutrofily genetika MeSH
- kolitida chemicky indukované imunologie MeSH
- kolon imunologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- makrofágy imunologie MeSH
- mediátory zánětu metabolismus MeSH
- metaloproteinasy secernované do matrix genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- pohyb buněk MeSH
- přirozená imunita MeSH
- progrese nemoci MeSH
- síran dextranu MeSH
- střevní sliznice imunologie patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- DNA primery MeSH
- DNA virů analýza chemie izolace a purifikace MeSH
- genom virový MeSH
- molekulární sekvence - údaje MeSH
- profágy genetika izolace a purifikace klasifikace MeSH
- stafylokokové bakteriofágy genetika izolace a purifikace MeSH
- Staphylococcus aureus klasifikace virologie MeSH
- Publikační typ
- techniky in vitro MeSH
