MMP-19 deficiency causes aggravation of colitis due to defects in innate immune cell function

Mucosal Immunol. 2016 Jul;9(4):974-85. doi: 10.1038/mi.2015.117. Epub 2015 Nov 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Cells, Cultured
  • Chemokine CX3CL1 / metabolism*
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colon / immunology*
  • Cytokines / metabolism
  • Dextran Sulfate
  • Disease Progression
  • Humans
  • Immunity, Innate
  • Inflammation Mediators / metabolism
  • Inflammatory Bowel Diseases / immunology*
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / pathology
  • Macrophages / immunology*
  • Matrix Metalloproteinases, Secreted / genetics
  • Matrix Metalloproteinases, Secreted / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration / genetics


  • Chemokine CX3CL1
  • Cx3cl1 protein, mouse
  • Cytokines
  • Inflammation Mediators
  • Dextran Sulfate
  • Matrix Metalloproteinases, Secreted
  • matrix metalloproteinase 19