Inhibition of Gelatinase B (Matrix Metalloprotease-9) Activity Reduces Cellular Inflammation and Restores Function of Transplanted Pancreatic Islets

Lingwal, Neelam; Padmasekar, Manju; Samikannu, Balaji; Bretzel, Reinhard G.; Preissner, Klaus T.; Linn, Thomas

doi:10.2337/db11-1143

Cited by 17 publications

(14 citation statements)

References 36 publications

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“…Overall, these results are in line with the growing number of reports supporting key roles for MMP-9 on leukocyte recruitment into inflamed tissues. [7-9, 11, 14, 22-24]…”

Section: Discussionmentioning

confidence: 99%

“…[7] While newly synthesized adhesion molecules provide leukocyte attachment to the vascular endothelium, matrix metalloproteinases (MMPs) facilitate their movement across vascular barriers. Among the different MMPs, MMP-9, an inducible enzyme expressed primarily by leukocytes, has been growingly recognized in pathologies that require disruption of basement membranes, multiple sclerosis,[8] postoperative ileus,[9] kidney IRI,[10] islet transplantation,[11] and acute small-for-size liver graft Injury. [12]…”

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confidence: 99%

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MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury

Kato¹,

Kuriyama²,

Duarte³

et al. 2014

Journal of Hepatology

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Background & Aims: Organ shortage has led to the use of steatotic livers in transplantation, despite their elevated susceptibility to ischemia/reperfusion injury (IRI). Matrix metalloproteinase-9 (MMP-9), an inducible gelatinase, is emerging as a central mediator of leukocyte traffic into inflamed tissues. However, its role in steatotic hepatic IRI has yet to be demonstrated. Methods: We examined the function of MMP-9 in mice fed with a high-fat diet (HFD), which developed approximately 50% hepatic steatosis, predominantly macrovesicular, prior to partial hepatic IRI. Results: The inability of MMP-9−/− deficient steatotic mice to express MMP-9 significantly protected these mice from liver IRI. Compared to fatty controls, MMP-9−/− steatotic livers showed significantly reduced leukocyte infiltration, proinflammatory cytokine expression, and liver necrosis. Loss of MMP-9 activity preserved platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, a modulator of vascular integrity at the endothelial cell–cell junctions in steatotic livers after IRI. Using in vitro approaches, we show that targeted inhibition of MMP-9 sheltered the extracellular portion of PECAM-1 from proteolytic processing, and disrupted leukocyte migration across this junctional molecule. Moreover, the evaluation of distinct parameters of regeneration, proliferating cell nuclear antigen (PCNA) and histone H3 phosphorylation (pH3), provided evidence that hepatocyte progression into S phase and mitosis was notably enhanced in MMP-9−/− steatotic livers after IRI. Conclusion: MMP-9 activity disrupts vascular integrity at least partially through a PECAM-1 dependent mechanism and interferes with regeneration of steatotic livers after IRI. Our novel findings establish MMP-9 as an important mediator of steatotic liver IRI.

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“…Overall, these results are in line with the growing number of reports supporting key roles for MMP-9 on leukocyte recruitment into inflamed tissues. [7-9, 11, 14, 22-24]…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury

Kato¹,

Kuriyama²,

Duarte³

et al. 2014

Journal of Hepatology

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“…Mmp9 À/À have been shown to have a defect in their growth plates, 30 resulting in slight growth retardation and smaller body size (Supplemental Table S2 [31][32][33][34][35][36][37][38][39][40][41][42]. The size of the pancreas in relation to the total body weight was, however, unaffected by the gelatinase deficiency (WT versus Mmp9 À/À ; 0.96 AE 0.06% versus 0.86 AE 0.02% pancreas weight of total b.w., P Z 0.14).…”

Section: The Morphology Of Islets In Mmp-9edeficient Mice Is Unchangedmentioning

confidence: 99%

Matrix Metalloproteinase-9 Is Essential for Physiological Beta Cell Function and Islet Vascularization in Adult Mice

Christoffersson

Waldén

Sandberg

et al. 2015

The American Journal of Pathology

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The availability of paracrine factors in the islets of Langerhans, and the constitution of the beta cell basement membrane can both be affected by proteolytic enzymes. This study aimed to investigate the effects of the extracellular matrix-degrading enzyme gelatinase B/matrix metalloproteinase-9 (Mmp-9) on islet function in mice. Islet function of Mmp9-deficient (Mmp9(-/-)) mice and their wild-type littermates was evaluated both in vivo and in vitro. The pancreata of Mmp9(-/-) mice did not differ from wild type in islet mass or distribution. However, Mmp9(-/-) mice had an impaired response to a glucose load in vivo, with lower serum insulin levels. The glucose-stimulated insulin secretion was reduced also in vitro in isolated Mmp9(-/-) islets. The vascular density of Mmp9(-/-) islets was lower, and the capillaries had fewer fenestrations, whereas the islet blood flow was threefold higher. These alterations could partly be explained by compensatory changes in the expression of matrix-related proteins. This in-depth investigation of the effects of the loss of MMP-9 function on pancreatic islets uncovers a deteriorated beta cell function that is primarily due to a shift in the beta cell phenotype, but also due to islet vascular aberrations. This likely reflects the importance of a normal islet matrix turnover exerted by MMP-9, and concomitant release of paracrine factors sequestered on the matrix.

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“…To inhibit chemotaxis induced by MMPs, the MMP inhibitor GM6001 (10 μmol/L; Santa Cruz Biotechnology, Inc.) was used, as described previously. 23 GM6001 inhibits MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MT-MMP1, and MMP-26.…”

Section: Methodsmentioning

confidence: 98%

Ex vivo Pretreatment of Islets with Mitomycin C

et al. 2017

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Strategies to reduce the immunogenicity of pancreatic islets and to prevent the activation of proinflammatory events are essential for successful islet engraftment. Pretransplant islet culture presents an opportunity for preconditioning to improve outcomes of islet transplantation. We previously demonstrated that ex vivo mitomycin C (MMC) pretreatment and subsequent culture significantly prolonged graft survival. Fully understanding the biological process of pretreatment could result in the development of a protocol to improve the survival of islet grafts. Microarrays were employed to conduct a comprehensive analysis of genes expressed in untreated or MMC-treated rat islets that were subsequently cultured for 3 d. A bioinformatics software was used to identify biological processes that were most affected by MMC pretreatment, and validation studies, including in vivo and in vitro assay, were performed. The gene expression analysis identified significant downregulation of annotated functions associated with cellular movement and revealed significant downregulation of multiple genes encoding proinflammatory mediators with chemotactic activity. Validation studies revealed significantly decreased levels of interleukin 6 (IL-6), monocyte chemoattractant protein 3 (MCP-3), and matrix metallopeptidase 2 (MMP2) in culture supernatants of MMC-treated islets compared with controls. Moreover, we showed the suppression of leukocyte chemotactic activity of MMC-treated islets in vitro. We also showed that MMC-treated islets secreted lower levels of chemoattractants that synergistically reduced the immunogenic potential of islets. Histological and immunohistochemical analyses of the implant site revealed that infiltration of monocytes, CD3-positive T cells, and B cells was decreased in MMC-treated islets. In conclusion, the ex vivo pretreatment of islets with MMC and subsequent culture can reduce the immunogenic potential and prolong the survival of islet grafts by inducing the suppression of multiple leukocyte chemotactic factors.

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Inhibition of Gelatinase B (Matrix Metalloprotease-9) Activity Reduces Cellular Inflammation and Restores Function of Transplanted Pancreatic Islets

Cited by 17 publications

References 36 publications

MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury

MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury

Matrix Metalloproteinase-9 Is Essential for Physiological Beta Cell Function and Islet Vascularization in Adult Mice

Ex vivo Pretreatment of Islets with Mitomycin C

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