Selective ablation of matrix metalloproteinase-2 exacerbates experimental colitis: Contrasting role of gelatinases in the pathogenesis of colitis

Pallavi Garg, Mauricio Rojas, Anupama Ravi, Katrina Bockbrader, Steven Epstein, Matam Vijay-Kumar, Andrew T. Gewirtz, Didier Merlin, Shanthi V. Sitaraman

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4103-4112
Number of pages10
JournalJournal of Immunology
Volume177
Issue number6
DOIs
StatePublished - Sep 15 2006

Fingerprint

Gelatinases
Matrix Metalloproteinase 2
Colitis
Matrix Metalloproteinase 9
Dextran Sulfate
Mucous Membrane
Bone Marrow
Inflammation Mediators
Salmonella enterica
Matrix Metalloproteinases
Inflammatory Bowel Diseases
Bone Marrow Cells
Peroxidase
Histology
Animal Models
Epithelial Cells
Inflammation

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Garg, Pallavi ; Rojas, Mauricio ; Ravi, Anupama ; Bockbrader, Katrina ; Epstein, Steven ; Vijay-Kumar, Matam ; Gewirtz, Andrew T. ; Merlin, Didier ; Sitaraman, Shanthi V. / Selective ablation of matrix metalloproteinase-2 exacerbates experimental colitis : Contrasting role of gelatinases in the pathogenesis of colitis. In: Journal of Immunology. 2006 ; Vol. 177, No. 6. pp. 4103-4112.
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abstract = "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.",
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Garg, P, Rojas, M, Ravi, A, Bockbrader, K, Epstein, S, Vijay-Kumar, M, Gewirtz, AT, Merlin, D & Sitaraman, SV 2006, 'Selective ablation of matrix metalloproteinase-2 exacerbates experimental colitis: Contrasting role of gelatinases in the pathogenesis of colitis', Journal of Immunology, vol. 177, no. 6, pp. 4103-4112. https://doi.org/10.4049/jimmunol.177.6.4103

Selective ablation of matrix metalloproteinase-2 exacerbates experimental colitis : Contrasting role of gelatinases in the pathogenesis of colitis. / Garg, Pallavi; Rojas, Mauricio; Ravi, Anupama; Bockbrader, Katrina; Epstein, Steven; Vijay-Kumar, Matam; Gewirtz, Andrew T.; Merlin, Didier; Sitaraman, Shanthi V.

In: Journal of Immunology, Vol. 177, No. 6, 15.09.2006, p. 4103-4112.

Research output: Contribution to journalArticle

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T1 - Selective ablation of matrix metalloproteinase-2 exacerbates experimental colitis

T2 - Contrasting role of gelatinases in the pathogenesis of colitis

AU - Garg, Pallavi

AU - Rojas, Mauricio

AU - Ravi, Anupama

AU - Bockbrader, Katrina

AU - Epstein, Steven

AU - Vijay-Kumar, Matam

AU - Gewirtz, Andrew T.

AU - Merlin, Didier

AU - Sitaraman, Shanthi V.

PY - 2006/9/15

Y1 - 2006/9/15

N2 - 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.

AB - 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.

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