Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival
In type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in β-cells. Nonetheless, the temporality of the events triggered and the role of different ROS sources remain unclear. Isolated islets from C57BL/...
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doaj-b169413cbb0347bd9d392b45638c86d92021-08-26T13:28:56ZengMDPI AGAntioxidants2076-39212021-08-01101305130510.3390/antiox10081305Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and SurvivalEloisa A. Vilas-Boas0Christopher Carlein1Lisa Nalbach2Davidson C. Almeida3Emmanuel Ampofo4Angelo R. Carpinelli5Leticia P. Roma6Fernanda Ortis7Center for Human and Molecular Biology (ZHMB), Department of Biophysics, Saarland University, 66424 Homburg, GermanyCenter for Human and Molecular Biology (ZHMB), Department of Biophysics, Saarland University, 66424 Homburg, GermanyInstitute for Clinical and Experimental Surgery, Saarland University, 66424 Homburg, GermanyDepartment of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, SP, BrazilInstitute for Clinical and Experimental Surgery, Saarland University, 66424 Homburg, GermanyDepartment of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, SP, BrazilCenter for Human and Molecular Biology (ZHMB), Department of Biophysics, Saarland University, 66424 Homburg, GermanyDepartment of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, SP, BrazilIn type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in β-cells. Nonetheless, the temporality of the events triggered and the role of different ROS sources remain unclear. Isolated islets from C57BL/6J wild-type (WT), NOX1 KO and NOX2 KO mice were exposed to a PIC combination. We show that cytokines increase O<sub>2</sub><sup>•−</sup> production after 2 h in WT and NOX1 KO but not in NOX2 KO islets. Using transgenic mice constitutively expressing a genetically encoded compartment specific H<sub>2</sub>O<sub>2</sub> sensor, we show, for the first time, a transient increase of cytosolic/nuclear H<sub>2</sub>O<sub>2</sub> in islet cells between 4 and 5 h during cytokine exposure. The H<sub>2</sub>O<sub>2</sub> increase coincides with the intracellular NAD(P)H decrease and is absent in NOX2 KO islets. NOX2 KO confers better glucose tolerance and protects against cytokine-induced islet secretory dysfunction and death. However, NOX2 absence does not counteract the cytokine effects in ER Ca<sup>2+</sup> depletion, Store-Operated Calcium Entry (SOCE) increase and ER stress. Instead, the activation of ER stress precedes H<sub>2</sub>O<sub>2</sub> production. As early NOX2-driven ROS production impacts β-cells’ function and survival during insulitis, NOX2 might be a potential target for designing therapies against early β-cell dysfunction in the context of T1D onset.https://www.mdpi.com/2076-3921/10/8/1305β-cellER stresshydrogen peroxideinsulitisNADPH oxidaseoxidative stress |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Eloisa A. Vilas-Boas Christopher Carlein Lisa Nalbach Davidson C. Almeida Emmanuel Ampofo Angelo R. Carpinelli Leticia P. Roma Fernanda Ortis |
spellingShingle |
Eloisa A. Vilas-Boas Christopher Carlein Lisa Nalbach Davidson C. Almeida Emmanuel Ampofo Angelo R. Carpinelli Leticia P. Roma Fernanda Ortis Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival Antioxidants β-cell ER stress hydrogen peroxide insulitis NADPH oxidase oxidative stress |
author_facet |
Eloisa A. Vilas-Boas Christopher Carlein Lisa Nalbach Davidson C. Almeida Emmanuel Ampofo Angelo R. Carpinelli Leticia P. Roma Fernanda Ortis |
author_sort |
Eloisa A. Vilas-Boas |
title |
Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival |
title_short |
Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival |
title_full |
Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival |
title_fullStr |
Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival |
title_full_unstemmed |
Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival |
title_sort |
early cytokine-induced transient nox2 activity is er stress-dependent and impacts β-cell function and survival |
publisher |
MDPI AG |
series |
Antioxidants |
issn |
2076-3921 |
publishDate |
2021-08-01 |
description |
In type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in β-cells. Nonetheless, the temporality of the events triggered and the role of different ROS sources remain unclear. Isolated islets from C57BL/6J wild-type (WT), NOX1 KO and NOX2 KO mice were exposed to a PIC combination. We show that cytokines increase O<sub>2</sub><sup>•−</sup> production after 2 h in WT and NOX1 KO but not in NOX2 KO islets. Using transgenic mice constitutively expressing a genetically encoded compartment specific H<sub>2</sub>O<sub>2</sub> sensor, we show, for the first time, a transient increase of cytosolic/nuclear H<sub>2</sub>O<sub>2</sub> in islet cells between 4 and 5 h during cytokine exposure. The H<sub>2</sub>O<sub>2</sub> increase coincides with the intracellular NAD(P)H decrease and is absent in NOX2 KO islets. NOX2 KO confers better glucose tolerance and protects against cytokine-induced islet secretory dysfunction and death. However, NOX2 absence does not counteract the cytokine effects in ER Ca<sup>2+</sup> depletion, Store-Operated Calcium Entry (SOCE) increase and ER stress. Instead, the activation of ER stress precedes H<sub>2</sub>O<sub>2</sub> production. As early NOX2-driven ROS production impacts β-cells’ function and survival during insulitis, NOX2 might be a potential target for designing therapies against early β-cell dysfunction in the context of T1D onset. |
topic |
β-cell ER stress hydrogen peroxide insulitis NADPH oxidase oxidative stress |
url |
https://www.mdpi.com/2076-3921/10/8/1305 |
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