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Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors

The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiati...

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Autores principales: Nigi, Laura, Brusco, Noemi, Grieco, Giuseppina E., Fignani, Daniela, Licata, Giada, Formichi, Caterina, Aiello, Elena, Marselli, Lorella, Marchetti, Piero, Krogvold, Lars, Jorgensen, Knut Dahl, Sebastiani, Guido, Dotta, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8963204/
https://www.ncbi.nlm.nih.gov/pubmed/35359976
http://dx.doi.org/10.3389/fimmu.2022.833141
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author Nigi, Laura
Brusco, Noemi
Grieco, Giuseppina E.
Fignani, Daniela
Licata, Giada
Formichi, Caterina
Aiello, Elena
Marselli, Lorella
Marchetti, Piero
Krogvold, Lars
Jorgensen, Knut Dahl
Sebastiani, Guido
Dotta, Francesco
author_facet Nigi, Laura
Brusco, Noemi
Grieco, Giuseppina E.
Fignani, Daniela
Licata, Giada
Formichi, Caterina
Aiello, Elena
Marselli, Lorella
Marchetti, Piero
Krogvold, Lars
Jorgensen, Knut Dahl
Sebastiani, Guido
Dotta, Francesco
author_sort Nigi, Laura
collection PubMed
description The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiation associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of nondiabetic and T1D donors is still missing. In the present study, we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 nondiabetic autoantibody-negative, 2 nondiabetic autoantibody-positive, 8 recent-onset, and 2 long-standing T1D). In nondiabetic control donors, MDA5 was expressed both in α- and β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate of MDA5-glucagon with respect to MDA5-insulin in comparison to nondiabetic controls; such increase was more pronounced in recent-onset with respect to long-standing T1D donors. Of note, an increased colocalization rate of MDA5-glucagon was found in insulin-deficient-islets (IDIs) with respect to insulin-containing-islets (ICIs). Strikingly, we detected the presence of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, presumably due to dedifferentiation or neogenesis phenomena. These clusters were identified exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D. In conclusion, we showed that MDA5 is preferentially expressed in α-cells, and its expression is increased in recent-onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells.
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spelling pubmed-89632042022-03-30 Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors Nigi, Laura Brusco, Noemi Grieco, Giuseppina E. Fignani, Daniela Licata, Giada Formichi, Caterina Aiello, Elena Marselli, Lorella Marchetti, Piero Krogvold, Lars Jorgensen, Knut Dahl Sebastiani, Guido Dotta, Francesco Front Immunol Immunology The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiation associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of nondiabetic and T1D donors is still missing. In the present study, we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 nondiabetic autoantibody-negative, 2 nondiabetic autoantibody-positive, 8 recent-onset, and 2 long-standing T1D). In nondiabetic control donors, MDA5 was expressed both in α- and β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate of MDA5-glucagon with respect to MDA5-insulin in comparison to nondiabetic controls; such increase was more pronounced in recent-onset with respect to long-standing T1D donors. Of note, an increased colocalization rate of MDA5-glucagon was found in insulin-deficient-islets (IDIs) with respect to insulin-containing-islets (ICIs). Strikingly, we detected the presence of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, presumably due to dedifferentiation or neogenesis phenomena. These clusters were identified exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D. In conclusion, we showed that MDA5 is preferentially expressed in α-cells, and its expression is increased in recent-onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells. Frontiers Media S.A. 2022-03-11 /pmc/articles/PMC8963204/ /pubmed/35359976 http://dx.doi.org/10.3389/fimmu.2022.833141 Text en Copyright © 2022 Nigi, Brusco, Grieco, Fignani, Licata, Formichi, Aiello, Marselli, Marchetti, Krogvold, Jorgensen, Sebastiani and Dotta https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Nigi, Laura
Brusco, Noemi
Grieco, Giuseppina E.
Fignani, Daniela
Licata, Giada
Formichi, Caterina
Aiello, Elena
Marselli, Lorella
Marchetti, Piero
Krogvold, Lars
Jorgensen, Knut Dahl
Sebastiani, Guido
Dotta, Francesco
Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors
title Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors
title_full Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors
title_fullStr Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors
title_full_unstemmed Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors
title_short Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors
title_sort increased expression of viral sensor mda5 in pancreatic islets and in hormone-negative endocrine cells in recent onset type 1 diabetic donors
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8963204/
https://www.ncbi.nlm.nih.gov/pubmed/35359976
http://dx.doi.org/10.3389/fimmu.2022.833141
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