The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of NOD mice

Hultcrantz, Monica; Jacobson, S.; Hill, Natasha J.; Santamaría, Pere; Flodström‐Tullberg, Malin

doi:10.1007/s00125-008-1193-7

Cited by 10 publications

(4 citation statements)

References 40 publications

(65 reference statements)

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“…Several observations have led to the suggestion that pro-inflammatory cytokines secreted by macrophages and T lymphocytes infiltrating the pancreatic islets may contribute to the development of type 1 diabetes. Recent studies by us and others have provided further support for the hypothesis that cytokines contribute to type 1 diabetes by acting directly on the beta cells [3][4][5][6].…”

Section: Introductionmentioning

confidence: 83%

Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

Zaitseva

Hultcrantz

Sharoyko

et al. 2009

Cell. Mol. Life Sci.

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Pancreatic beta cell damage caused by proinflammatory cytokines interleukin-1beta (IL-1beta), interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNgamma-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1beta, IFNgamma, TNFalpha. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFNgamma in beta cells. In summary, we show that interference with IFNgamma signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death.

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Section: Introductionmentioning

confidence: 83%

Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

Zaitseva

Hultcrantz

Sharoyko

et al. 2009

Cell. Mol. Life Sci.

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“…The generation and screening of the Socs1-tg mouse model on a NOD background have been described previously [13,14,28,29]. In brief, these mice express Socs1 under the control of the human insulin promotor and, as a result of a failing interferon-induced antiviral defence in the beta cells, develop diabetes within 5-11 days after infection with either CVB3 or CVB4 [13,14].…”

Section: Methodsmentioning

confidence: 99%

Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice

et al. 2013

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Aims/hypothesis Enterovirus (e.g. Coxsackie B virus serotypes [CVBs]) infections may be associated with development of type 1 diabetes. Studies conducted in several European countries have, however, shown an inverse correlation between the incidence of type 1 diabetes and the prevalence of enterovirus infections. These findings could in part be explained by an extension of the poliovirus hypothesis, suggesting that the absence of maternally transferred antibodies protecting offspring from early infection increases the risk for diabetes development. Experimental evidence supporting this hypothesis in type 1 diabetes is, however, lacking. As maternally transferred protection from infection is a crucial component of the extended poliovirus hypothesis, we here tested the hypothesis that previously infected females transfer protection against infection and diabetes to offspring.Methods The induction of CVB-specific maternal antibodies and transfer of protection from virus infection, replication and development of virus-induced diabetes to offspring was assessed using NOD and Socs1-transgenic NOD mice. Results Infected mice produced neutralising antibodies to CVB. Offspring from infected females were positive for neutralising antibodies and were strongly protected from both infection and experimental diabetes. Conclusions/interpretation Our study shows that maternally transferred antibodies protect offspring from enterovirus infection and virus-induced diabetes. This suggests that the absence of maternally provided protection increases the risk for severe outcomes after an enterovirus infection in offspring. Moreover, our findings may have implications for the design of prospective studies aimed at investigating the possible role of enterovirus infections in the aetiology of human type 1 diabetes.

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“…CXCL10 is produced by pancreatic islet cells upon inflammatory stress (5) and is specifically recognized by C-X-C Motif Chemokine Receptor 3 (CXCR3) which is expressed by activated T-lymphocytes and other immune cells (4,6). Several reports demonstrated that CXCL10 plays an important role in the natural history of T1D mainly through the attraction of autoreactive T-lymphocytes to the islets, thus leading to the subsequent destruction of pancreatic beta-cells (6)(7)(8)(9)(10)(11)(12). Of note, although still debated, CXCL10 has been proposed as a possible therapeutic target, supported by several studies showing the beneficial effects of CXCL10 inhibition (13).…”

Section: Introductionmentioning

confidence: 99%

Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes

et al. 2020

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C-X-C Motif Chemokine Ligand 10 (CXCL10) is a pro-inflammatory chemokine specifically recognized by the ligand receptor CXCR3 which is mostly expressed in T-lymphocytes. Although CXCL10 expression and secretion have been widely associated to pancreatic islets both in non-obese diabetic (NOD) mice and in human type 1 diabetic (T1D) donors, the specific expression pattern among pancreatic endocrine cell subtypes has not been clarified yet. Therefore, the purpose of this study was to shed light on the pancreatic islet expression of CXCL10 in NOD, in C57Bl/6J and in NOD-SCID mice as well as in human T1D pancreata from new-onset T1D patients (DiViD study) compared to non-diabetic multiorgan donors from the INNODIA European Network for Pancreatic Organ Donors with Diabetes (EUnPOD). CXCL10 was expressed in pancreatic islets of normoglycaemic and new-onset diabetic NOD mice but not in C57Bl/6J and NOD-SCID mice. CXCL10 expression was increased in pancreatic islets of new-onset diabetic NOD mice compared to normoglycaemic NOD mice. In NOD mice, CXCL10 colocalized both with insulin and glucagon. Interestingly, CXCL10-glucagon colocalization rate was significantly increased in diabetic vs. normoglycaemic NOD mouse islets, indicating an increased expression of CXCL10 also in alpha-cells. CXCL10 was expressed in pancreatic islets of T1D patients but not in non-diabetic donors. The analysis of the expression pattern of CXCL10 in human T1D pancreata from DiViD study, revealed an increased colocalization rate with glucagon compared to insulin. Of note, CXCL10 was also expressed in alpha-cells residing in insulin-deficient islets (IDI), suggesting that CXCL10 expression in alpha cells is not driven by residual beta-cells and therefore may represent an independent phenomenon. In conclusion, we show that in T1D CXCL10 is expressed by alpha-cells both in NOD mice and in T1D patients, thus pointing to an additional novel role for alpha-cells in T1D pathogenesis and progression.

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The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of NOD mice

Cited by 10 publications

References 40 publications

Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice

Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes

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