title: MMP-19 deficiency causes aggravation of colitis due to defects in innate immune cell function.
abstract: 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.
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.|Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
authors.forename: R
authors.initials: R
authors.lastname: Brauer
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Tureckova
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.
authors.forename: I
authors.initials: I
authors.lastname: Kanchev
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Khoylou
authors.affiliation: Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Skarda
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Prochazka
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.
authors.forename: F
authors.initials: F
authors.lastname: Spoutil
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.
authors.forename: I M
authors.initials: IM
authors.lastname: Beck
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.
authors.forename: O
authors.initials: O
authors.lastname: Zbodakova
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.|Faculty of Sciences, Charles University in Prague, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Kasparek
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Korinek
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Chalupsky
authors.affiliation: Institute of Biomedicine and Biocenter of Oulu, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Karhu
authors.affiliation: Institute of Biomedicine and Biocenter of Oulu, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: K-H
authors.initials: KH
authors.lastname: Herzig
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Hajduch
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.|Institute of Molecular Genetics of the ASCR, Laboratory of Integrative Biology, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Gregor
authors.affiliation: Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.
authors.forename: R
authors.initials: R
authors.lastname: Sedlacek
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D018450:Disease Progression; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics
chemical_list: D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D016264:Dextran Sulfate; D053505:Matrix Metalloproteinases, Secreted; C108362:matrix metalloproteinase 19