The Peri-islet Basement Membrane, a Barrier to Infiltrating Leukocytes in Type 1 Diabetes in Mouse and Human
| Autor: | Jeannine Wegner, Lydia Sorokin, Christopher M. Overall, Ekkehard Weber, Dan Holmberg, Reinhild Kappelhoff, Eva Korpos, Susanna Cardell, Nadir Kadri |
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| Rok vydání: | 2013 |
| Předmět: |
endocrine system
medicine.medical_specialty endocrine system diseases Endocrinology Diabetes and Metabolism Protein Array Analysis Proteinase Inhibitory Proteins Secretory Biology Basement Membrane Cathepsin C Extracellular matrix Islets of Langerhans Mice Interstitial matrix Mice Inbred NOD Internal medicine Internal Medicine medicine Animals Humans NOD mice Inflammation Basement membrane Online Letters to the Editor geography geography.geographical_feature_category Macrophages Pancreatic islets medicine.disease Islet Cathepsins Molecular biology Extracellular Matrix Transplantation Chemotaxis Leukocyte Cathepsin W Diabetes Mellitus Type 1 Endocrinology medicine.anatomical_structure Islet Studies Insulitis |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db12-0432 |
| Popis: | We provide the first comprehensive analysis of the extracellular matrix (ECM) composition of peri-islet capsules, composed of the peri-islet basement membrane (BM) and subjacent interstitial matrix (IM), in development of type 1 diabetes in NOD mice and in human type 1 diabetes. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. Stereological analyses reveal a correlation between incidence of insulitis and the number of islets showing loss of peri-islet BM versus islets with intact BMs, suggesting that leukocyte penetration of the peri-islet BM is a critical step. Protease- and protease inhibitor–specific microarray analyses (CLIP-CHIP) of laser-dissected leukocyte infiltrated and noninfiltrated pancreatic islets and confirmatory quantitative real time PCR and protein analyses identified cathepsin S, W, and C activity at sites of leukocyte penetration of the peri-islet BM in association with a macrophage subpopulation in NOD mice and human type 1 diabetic samples and, hence, potentially a novel therapeutic target specifically acting at the islet penetration stage. Interestingly, the peri-islet BM and underlying IM are reconstituted once inflammation subsides, indicating that the peri-islet BM-producing cells are not lost due to the inflammation, which has important ramifications to islet transplantation studies. |
| Databáze: | OpenAIRE |
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