Inhibition of Gelatinase B (Matrix Metalloprotease-9) Activity Reduces Cellular Inflammation and Restores Function of Transplanted Pancreatic Islets
- Neelam Lingwal1,
- Manju Padmasekar1,
- Balaji Samikannu1,
- Reinhard G. Bretzel1,
- Klaus T. Preissner2 and
- Thomas Linn1⇓
- 1Third Medical Department, Faculty of Medicine, Justus-Liebig University, Giessen, Germany
- 2Institute for Biochemistry, Faculty of Medicine, Justus-Liebig University, Giessen, Germany
- Corresponding author: Thomas Linn, .
Islet transplantation provides an approach to compensate for loss of insulin-producing cells in patients with type 1 diabetes. However, the intraportal route of transplantation is associated with instant inflammatory reactions to the graft and subsequent islet destruction as well. Although matrix metalloprotease (MMP)-2 and -9 are involved in both remodeling of extracellular matrix and leukocyte migration, their influence on the outcome of islet transplantation has not been characterized. We observed comparable MMP-2 mRNA expressions in control and transplanted groups of mice, whereas MMP-9 mRNA and protein expression levels increased after islet transplantation. Immunostaining for CD11b (Mac-1)-expressing leukocytes (macrophage, neutrophils) and Ly6G (neutrophils) revealed substantially reduced inflammatory cell migration into islet-transplanted liver in MMP-9 knockout recipients. Moreover, gelatinase inhibition resulted in a significant increase in the insulin content of transplanted pancreatic islets and reduced macrophage and neutrophil influx compared with the control group. These results indicate that the increase of MMP-9 expression and activity after islet transplantation is directly related to enhanced leukocyte migration and that early islet graft survival can be improved by inhibiting MMP-9 (gelatinase B) activity.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1143/-/DC1.
- Received August 17, 2011.
- Accepted March 9, 2012.
- © 2012 by the American Diabetes Association.
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