Laminins are composed of an α, β, and γ chain, and 5α, 4β, and 3γ laminin chains exist that combine to form at least 18 different isoforms. These results showed that IL‐33 treatment prevented islet allograft rejection and improved islet function. A layer of IM occurred immediately subjacent to the peri-islet BM and was composed of the fibrillar collagens (types I and III; Fig. This is in accordance with enhanced β-cell apoptosis due to autoimmune attack, thereby validating our sample preparation. D: Stereological analyses of pancreatic sections from 5- and 14-week-old normoglycemic and 21-week-old diabetic NOD mice (n = 3/each group) were used to quantify the number of islets with intact peri-islet BMs (healthy islets and islets in peri-insulitis stage) vs. invaded islets showing loss of peri-islet BM staining. 2D). Antibodies were characterized by enzyme-linked immunosorbent assay, tissue distribution as determined by immunofluorescence microscopy, and by Western blot analyses (25). 3A–C). Lymphocyte Infiltration in Pancreatic Islets Mediates [beta]-Cell Proliferation in NOD Mice Type 1 Diabetes (T1D), is a T- Type 1 Diabetes (T1D), is a T-cell mediated disease characterized by selective destruction of [beta]-cells. The pro-inflammatory TNF-a and VEGF content in islet grafted kidneys was significantly lowered by the treatment. CMV infection of the graft was only observed prior to complete graft failure. Matrix metalloproteinase (MMP)-2 and -9 activity in pancreas sections was detected, as previously described (19). Epub 2004 May 10. In vitro studies showed that cultured islets from Mkk3-/- and WT mice are equally susceptible to STZ and cytokine-induced apoptosis. We … Validation of CLIP-CHIP data at the protein level by immunofluorescence in NOD samples. 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. MLD-STZ in wild type mice induced islet leukocyte infiltration, cytokine production, beta-cell apoptosis, and hyperglycemia. Immunofluorescence staining of NOD 21-week-old pancreas sections for cathepsin C (A), cathepsin S (B), and cathepsin W (C) shows localization at sites where peri-islet BM staining is lost (arrows), as shown here by laminin (LM) γ1 staining. J Neuroimmunol. We therefore used diabetic NOD mice (aged >21 weeks) supplemented with subcutaneous insulin pellets to investigate whether reconstitution of the peri-islet BM indeed occurs after inflammation has subsided and what is the potential cellular source or sources of these BM proteins. Epub 2004 Oct 19. ACKNOWLEDGMENTS. 1999 May;12(3):167-76. doi: 10.1006/jaut.1998.0268. Islets were identified by vascular morphology and islet infiltration state was characterized as mild (0.1–30% of islet volume infiltrated by T cells) or advanced (30–60% of islet volume infiltrated by T cells) as previously described . Protease- and protease inhibitor–specific microar-ray analyses (CLIP-CHIP) of laser-dissected leukocyte … We show that the peri-capsular ECM is composed of a peri-islet BM embedded in an IM layer that interconnects with the surrounding blood vessels and exocrine tissue. Parallel analyses of the expression of the major ECM receptors revealed localization of Lutheran blood group glycoprotein and β-dystroglycan on endothelial cells and a weak immunosignal for β-dystroglycan on cells that were close to the peri-islet BM (Table 1). By implanting insulin capsules into diabetic NOD mice, we were able to observe the same phenomena and also identify the early formation of α-cell, glucagon+ clusters that were surrounded by a BM of the same composition as the peri-islet BM. The primary and secondary antibodies used are listed in Supplementary Table 1. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Combination treatment was effective against spontaneous disease when administered from 7 days of age but ineffective when initiated late in the prediabetic period (day 40 or 70). Here, we completely blocked adoptive transfer of diabetes and reduced spontaneous disease incidence from 71% to 17% by simultaneously administering a combination of antibodies directed against alpha4, beta2, and beta7 integrins and their ligands VCAM-1, MAdCAM-1, and ICAM-1 for 52 and 28 days, respectively. Using light-sheet imaging of a non-obese diabetic mouse model of type I diabetes, we also characterized the infiltration of CD45 (also known as PTPRC)-labeled leukocytes in islets. Statistical analyses were performed using two-way ANOVA. Collagen type IV is considered to be the structural basis of BMs, whereas the laminins impart specific signals to cells attached to or moving through BMs and are thereby responsible for biological activity. Additionally, FTY720 stimulated insulin secretion from isolated islets by approximately twofold under both normoglycemic and hyperglycemic conditions. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. This leukocyte infiltration is chiefly composed of T-cells (CD8+ and CD4+), but not macrophages (Bogdani et al. It also suggests the involvement of several proteases or of proteases with broad specificity. intra-islet leukocyte infiltration (Fig. W, weeks. This is consistent with the exclusive expression of cathepsins S and W by inflammatory cells (36,37) and broad cellular expression of cathepsin C (38), and may explain why only the BM and IM components of the peri-islet capsule are selectively lost and not BMs of peri-islet blood vessels or the acini of the exocrine pancreas, despite widespread leukocyte infiltration. 5A–C). In addition, cathepsins may be associated with degradation of endogenous inhibitors, resulting in increased activity of other proteases (49). Our data suggest that the ECM milieu influences the mode used by immune cells to infiltrate into tissues and raises novel possibilities for tissue-specific immune modulatory therapies. Quantitative analyses revealed significantly reduced mean fluorescence intensity of the peri-islet BM pan-laminin staining at sites of leukocyte invasion of islets and loss of insulin+ cells and that this correlates with disease progression, with a higher incidence of insulitis when more islets showed penetration of the peri-islet BM. Stereological analyses reveal a correla-tion 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. No or few leukocytes are present around such islets. At 14weeks, 40% of the small islets, but more than 80% of large islets, showed leukocyte infiltration. Cytokine Secretion, Leukocyte Infiltration, and Beta-Cell Damage. (A–C, nPOD case 6024, healthy pancreas) D: Schematic representation of the areas analyzed. 2018, Hull et al. Expression analysis specific for mouse cathepsin C, S, and W was performed. Flow cytometric enumeration of mononuclear cell populations infiltrating the islets of Langerhans in prediabetic NOD mice: development of a model of autoimmune insulitis for type I diabetes. 1F). Finally, histological examination for insulitis corroborated reduced leukocyte infiltration within the islets of the AIF1-silenced cohort relative to siScramble-treated NOD controls . 1. Animal models have little to teach us about type 1 diabetes: 2. No other potential conflicts of interest relevant to this article were reported. 2A and B; Table 1; Supplementary Video 2) and loss of insulin staining within islets (Fig. 2 ). 5H), which has been shown to be a ligand for β-cells, interaction with which enhances insulin production (28). Unable to load your collection due to an error, Unable to load your delegates due to an error. The Peri-islet Basement Membrane, a Barrier to Infiltrating Leukocytes in Type 1 Diabetes in Mouse and Human, Breeding of a non-obese, diabetic strain of mice, Type 1 diabetes: molecular, cellular and clinical immunology, Genetics, pathogenesis and clinical interventions in type 1 diabetes, Quantification and three-dimensional imaging of the insulitis-induced destruction of beta-cells in murine type 1 diabetes, Prevention of diabetes in nonobese diabetic mice mediated by CD1d-restricted nonclassical NKT cells, Developmental and pathogenic mechanisms of basement membrane assembly, Supramolecular assembly of basement membranes, Laminin-sulfatide binding initiates basement membrane assembly and enables receptor signaling in Schwann cells and fibroblasts, Tenascin-C in development and disease: gene regulation and cell function, Proteoglycans of the extracellular matrix and growth control, The impact of the extracellular matrix on inflammation, Endothelial basement membrane laminin alpha5 selectively inhibits T lymphocyte extravasation into the brain, Rapid leukocyte migration by integrin-independent flowing and squeezing, Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases, Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils, Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis, Distinct distribution of laminin and its integrin receptors in the pancreas, Blood vessels of human islets of Langerhans are surrounded by a double basement membrane, Unique basement membrane structure of human pancreatic islets: implications for beta-cell growth and differentiation, Molecular composition of the peri-islet basement membrane in NOD mice: a barrier against destructive insulitis, Immunohistochemical study of the pancreatic basement membrane in non obese diabetic mice (NOD) with spontaneous autoimmune insulitis, Monoclonal antibodies against laminin A chain fragment E3 and their effects on binding to cells and proteoglycan and on kidney development, Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis, Analysis of the degradome with the CLIP-CHIP microarray, The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation, Protease degradomics: mass spectrometry discovery of protease substrates and the CLIP-CHIP, a dedicated DNA microarray of all human proteases and inhibitors, Mechanism of cell surface activation of 72-kDa type IV collagenase. (G) PCNA + islet cells. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X. Quantitative real-time PCR was performed with 35 ng amplified cDNA per sample in an ABI PRISM 7300 cycler (Applied Biosystems, Darmstadt, Germany) using Brilliant SYBR Green QPCR Master Mix (Agilent Technologies). Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. The relationship between sex steroids, mega-islet formation, and leukocyte infiltration can be explained in different ways. The peri-islet BM is intact at sites where the leukocytes accumulate around the insulin+ islets (arrows in E) and is lost at sites of leukocyte invasion (arrowheads in E and F). Thus, initial events in T1D development leading to leukocyte infiltration into the pancreatic islets may be provoked by triggering of TLRs expressed by islet cells, which can respond to microbial signals by up-regulating the secretion of chemokines able to attract Th1 cells, macrophages, and DCs. Calcinaro F, Dionisi S, Marinaro M, Candeloro P, Bonato V, Marzotti S, Corneli RB, Ferretti E, Gulino A, Grasso F, De Simone C, Di Mario U, Falorni A, Boirivant M, Dotta F. Diabetologia. Given that transplantation experiments have highlighted the importance of the regenerative ability of the peri-islet capsule to long-term graft survival, this is a significant finding. NOD mice are one of the best-studied animal models of type 1 diabetes (2) due to similarities with the pathogenesis and genetics of human type 1 diabetes. É.K. D.H. and S.C. were involved in project development and contributed significantly to compilation of the manuscript. B: An optical section of a 3-dimensional projection of a whole-mount pancreatic islet shows in a simultaneous view of XY, XZ, and YZ planes, illustrating the peri-islet BM and endothelial BMs. Laminin α5 expression was stronger in the arterioles where smooth muscle cells express this chain in addition to endothelial cells (Fig. Further, cathepsin S has been reported to cleave the native triple-helical region of fibrillar collagen type I (48), which is present in the peri-islet IM. In contrast, Jnk1-/- mice were substantially protected from a loss of insulin producing cells and hyperglycemia in the MLD-STZ model despite a marked islet T cell and macrophage infiltrate. that islet architecture was lost, with only a few remaining insulin-positive cells and massive leukocyte infiltration. The authors thank Petra Blumberg and Sigmund Bundy (Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany) for their excellent technical assistance. Analyses of the laminin family of BM proteins together with endothelial cell markers revealed that the peri-islet BM was biochemically distinct to the BMs surrounding blood vessels and contained laminin α2, α4, β1, β2, γ1, γ2, and γ3 chains (Fig. 2 ). (A high-quality digital representation of this figure is available in the online issue.). labeled leukocytes in islets. Hence, reconstitution of the peri-islet BM may have important ramifications to islet transplantation studies. Because of the natural composition of islet‐like extracellular matrix (ECM) and its role in preventing leukocyte infiltration of pancreatic islets in the native pancreas, 18 we replaced ALG with a commercially available reagent, Matrigel (or MG), which resembles the composition of islet ECM. Adaptive Immunity and Pathogenesis of Diabetes: Insights Provided by the α4-Integrin Deficient NOD Mouse. The reduced neutrophil infiltration by thalidomide provides additional protection to the islet graft. The upregulation of MMP-14 is consistent with its proposed role in T-cell extravasation into the pancreas via CD44 cleavage (41) but can be excluded as a candidate for degradation of the peri-islet capsule. 1A and C). Hence, the possibility exists for a direct involvement of cathepsins in degradation of the peri-islet ECM. In the pancreatic head, only insulin− islets occurred, which were associated with little or no CD45+ cells, indicating that they represented islet remnants. Upon MLDS induction, Robo4‐deficiency resulted in increased pancreatic vascular permeability, leukocyte infiltration to the islets and islet apoptosis, associated with reduced insulin levels and faster diabetes development. MLD-STZ in wild type mice induced islet leukocyte infiltration, cytokine production, beta-cell apoptosis, and hyperglycemia. Limited information exists on the nature of the ECM of the pancreas and, in particular, on the composition of peri-islet capsule (20–22). A: Insulin+ and glucagon+ pancreatic islets are encased in the peri-islet BM. This indicates that leukocyte penetration of the peri-islet BM is a critical step in disease progression and potentially represents a new therapeutic target. 1D). Consistent with the results of the PAS staining, MLD-STZ Jnk1−/− mice also showed a macrophage and T cell infiltrate, the composition of which was not different to that seen in WT mice ( Fig. Cloning and expression of a cDNA coding for human cathepsin S, Characterization of murine cathepsin W and its role in cell-mediated cytotoxicity, Cloning and characterization of the cDNA encoding mouse dipeptidyl peptidase I (cathepsin C), Roles for cathepsins S, L, and B in insulitis and diabetes in the NOD mouse, Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading, Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas, Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice, Monitoring compartment-specific substrate cleavage by cathepsins B, K, L, and S at physiological pH and redox conditions, Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages, IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion, Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors, VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation, Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases, Integrin signaling via RGD peptides and anti-beta1 antibodies confers resistance to apoptosis in islets of Langerhans, Glucagon Resistance and Decreased Susceptibility to Diabetes in a Model of Chronic Hyperglucagonemia, Acyl-Ghrelin Influences Pancreatic β-Cell Function by Interference with K, Pancreatic β-Cell–Specific Deletion of VPS41 Causes Diabetes Due to Defects in Insulin Secretion, ADA Standards of Medical Care in Diabetes, Institutional Subscriptions and Site Licenses, Special Podcast Series: Therapeutic Inertia, Special Podcast Series: Influenza Podcasts, The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. hibiting diabetes and determined the fate of leukocytes respon- Serial sections were stained for CD4 and CD8 cells and macrophages, by the sible for the insulitis. Further, cathepsin S–null mice on a NOD background show significantly reduced incidence of diabetes (39). Several members of the cathepsin protease family, including cathepsin C, H, S, and W, showed a four- to sixfold increase in mRNA expression in infiltrated islets (Table 2), which was confirmed by quantitative real-time PCR (Supplementary Fig.
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