Selective ablation of matrix metalloproteinase-2 exacerbates experimental colitis: contrasting role of gelatinases in the pathogenesis of colitis.
The matrix metalloproteinases (MMPs), MMP-2 and MMP-9, share structural and substrate similarities and are up-regulated during human as well as animal models of inflammatory bowel disease. We recently demonstrated that epithelial-derived MMP-9 is an important mediator of inflammation and tissue damage in colitis. In this study, we examined the role of MMP-2 in acute colitis. Colitis was induced using two models, administration of dextran sodium sulfate (DSS) and Salmonella enterica subsp. serovar Typhimurium (S.T.). Bone marrow chimeras were performed using bone marrow cells from wild-type (WT) and MMP-2(-/-) mice. Colitis was evaluated by clinical symptoms, myeloperoxidase assay, and histology. MMP-2 protein expression and activity were up-regulated in WT mice treated with DSS or S.T. MMP-2(-/-) mice were highly susceptible to the development of colitis induced by DSS (or S.T.) compared with WT. During inflammation, MMP-2 expression was increased in epithelial cells as well as in the infiltrating immune cells. Bone marrow chimera demonstrated that mucosa-derived MMP-2 was required for its protective effects toward colitis. Furthermore, we demonstrate that severe colitis in MMP-2(-/-) is not due to a compensatory increase in MMP-9. Finally, we show that MMP-2 regulates epithelial barrier function. In contrast to MMP-9, mucosa-derived MMP-2 may be a critical host factor that is involved in the prevention or cessation of the host response to luminal pathogens or toxins, an important aspect of healing and tissue resolution. Together, our data suggest that a critical balance between the two gelatinases determines the outcome of inflammatory response during acute colitis.
Garg
Pallavi
P
Division of Digestive Diseases, Emory University, Atlanta, GA 30322, USA.
Rojas
Mauricio
M
Ravi
Anupama
A
Bockbrader
Katrina
K
Epstein
Steven
S
Vijay-Kumar
Matam
M
Gewirtz
Andrew T
AT
Merlin
Didier
D
Sitaraman
Shanthi V
SV
D000208:Acute Disease; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics* / Q000382:microbiology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012486:Salmonella typhimurium / Q000276:immunology
D016264:Dextran Sulfate; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9