Islet Abnormalities Associated with an Early Influx of Dendritic Cells and Macrophages in NOD and NODscid Mice

Rosmalen, Judith; Homo‐Delarche, Françoise; Durant, Sylvie; Kap, Marcel; Leenen, Pieter J. M.; Drexhage, Hemmo A.

doi:10.1038/labinvest.3780080

Cited by 55 publications

(53 citation statements)

References 42 publications

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“…Previous studies have reported inherent abnormalities in NOD islet development with an augmented increase in islet size and b-cell mass around weaning time (4 weeks) followed by an accelerated turnover of b-cells and their consequent death (33). This chronic b-cell stress phenomenon is independent of the autoimmune attack since it is also seen in the NOD.Scid background that lacks immune system components (31,34,35). Thus, to dissect PMP properties under an inherent chronic b-cell stress, we also used NOD.Scid mice to avoid the complexities that are accompanied by autoimmune reactions.…”

Section: Resultsmentioning

confidence: 95%

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

et al. 2014

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Endogenous pancreatic multipotent progenitors (PMPs) are ideal candidates for regenerative approaches to compensate for b-cell loss since their b-cell-producing capacities as well as strategic location would eliminate unnecessary invasive manipulations. However, little is known about the status and potentials of PMPs under diabetic conditions. Here we show that b-cell metabolic stress and hyperglycemia enhance the proliferation capacities of adult PMP cells and bias their production of progeny toward b-cells in mouse and human. These effects are dynamic and correlate with functional b-cell regeneration when conditions allow.

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Section: Resultsmentioning

confidence: 95%

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

et al. 2014

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“…It has been reported that NOD/SCID islets, although free of infiltrating lymphocytes, are indeed infiltrated by macrophages and dendritic cells (DC) [24]. Therefore, our observation that MHC class II mRNA is expressed in 9-to 10-week-old NOD/SCID mice at the same low frequency as in 3-week-old NOD mice strongly suggests that induction of I-A g7 is caused by the lymphocytic fraction of infiltrating cells, but not by infiltrating macrophages or DCs.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic NOD beta cells express MHC class II protein and the frequency of I-Ag7 mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes

et al. 2003

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Aims/hypothesis. In the NOD mouse model, attempts to show MHC class II expression by pancreatic beta cells were unsuccessful so far. We readdressed this question by analysing I-A g7 expression in single pancreatic beta cells. Methods. Single-cell multiplex RT PCR and singlecell immunofluorescence were used to study MHC class II expression in NOD and NOD/SCID beta cells. Results. Pancreatic beta cells from NOD mice express the I-A g7 protein as well as the corresponding mRNA. The frequency of MHC class II mRNA-expressing beta cells is drastically increased during the progression to overt diabetes. MHC class II protein is accumulated intracellularly, and invariant chain is co-expressed.

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“…This phenomenon was attributed, in part, to an enhanced macrophage-mediated immune response. In autoimmune diabetes, the infiltration of macrophages into islets precedes and is a prerequisite for lymphocytic insulitis and ␤-cell destruction (23,24,28). Macrophages mediate islet damage through ROS, NO, and cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

Emre

Hurtaud

Karaca

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Infiltration of inflammatory cells into pancreatic islets of Langerhans and selective destruction of insulin-secreting ␤-cells are characteristics of type 1 diabetes. Uncoupling protein 2 (UCP2) is a mitochondrial protein expressed in immune cells. UCP2 controls macrophage activation by modulating the production of mitochondrial reactive oxygen species (ROS) and MAPK signaling. We investigated the role of UCP2 on immune cell activity in type 1 diabetes in Ucp2-deficient mice. Using the model of multiple low-dose streptozotocin (STZ)-induced diabetes, we found that autoimmune diabetes was strongly accelerated in Ucp2-KO mice, compared with Ucp2-WT mice with increased intraislet lymphocytic infiltration. Macrophages from STZ-treated Ucp2-KO mice had increased IL-1␤ and nitric oxide (NO) production, compared with WT macrophages. Moreover, more macrophages were recruited in islets of STZ-treated Ucp2-KO mice, compared with Ucp2-WT mice. This finding also was accompanied by increased NO/ROS-induced damage. Altogether, our data show that inflammation is stronger in Ucp2-KO mice and islets, leading to the exacerbated disease in these mice. Our results highlight the mitochondrial protein UCP2 as a new player in autoimmune diabetes.inflammation ͉ nitric oxide M itochondria are important organelles for cellular functions, including ATP synthesis. Oxidative glucose metabolism in pancreatic ␤-cells increases the ATP/ADP ratio, leading to insulin release. Uncoupling protein 2 (UCP2) is a mitochondrial carrier protein expressed in pancreatic ␤-cells (1, 2) and immune cells (3,4).In pancreatic ␤-cells, UCP2 was reported to alter the yield of ATP synthesis from glucose, and it has been proposed as a negative regulator of glucose-stimulated insulin secretion (2). In other respects, there is much evidence for the influence of UCP2 on immune responses. First, Ucp2-KO mice exhibit increased resistance to a Toxoplasma gondii or Listeria monocytogenes infection (4, 5). Second, in an LDL receptor-null background, Ucp2-KO mice develop greater and more unstable atherosclerotic plaques than WT mice (6). Third, in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis, Ucp2-KO mice develop higher disease scores than Ucp2-WT mice (7). We showed that UCP2 regulates LPS-induced reactive oxygen species (ROS) signaling in macrophages (8). MAPK activation in Ucp2-KO macrophages is quicker and stronger than in WT macrophages (8), leading to increased nitric oxide (NO), cytokine production, and migration ability (8, 9). Consistent with these findings, overexpression of UCP2 in macrophages is associated with diminished NO production (10) and decreased migration capacity (11).Given the evidence for a role of UCP2 in the immune system, in macrophages, and in ␤-cell function, we investigated whether UCP2 affects the development of autoimmune diabetes by using the model of multiple low-dose of streptozotocin (STZ). In this report, we show that the absence of UCP2 renders animals more sensitive to the onset of diabetes in mice....

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Islet Abnormalities Associated with an Early Influx of Dendritic Cells and Macrophages in NOD and NODscid Mice

Cited by 55 publications

References 42 publications

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

Pancreatic NOD beta cells express MHC class II protein and the frequency of I-Ag7 mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes

Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

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