Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival

• Main Authors: Eloisa A. Vilas-Boas (Author), Christopher Carlein (Author), Lisa Nalbach (Author), Davidson C. Almeida (Author), Emmanuel Ampofo (Author), Angelo R. Carpinelli (Author), Leticia P. Roma (Author), Fernanda Ortis (Author)
• Format: Book
• Published: MDPI AG, 2021-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 O₂^•− 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 H₂O₂ sensor, we show, for the first time, a transient increase of cytosolic/nuclear H₂O₂ in islet cells between 4 and 5 h during cytokine exposure. The H₂O₂ 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 Ca²⁺ depletion, Store-Operated Calcium Entry (SOCE) increase and ER stress. Instead, the activation of ER stress precedes H₂O₂ 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.

Item Description

10.3390/antiox10081305
2076-3921