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

Autor(es)

Vilas-Boas, Eloisa A. ^{[1, 2]} ; Carlein, Christopher ^[2] ; Nalbach, Lisa ^[3] ; Almeida, Davidson C. ^[4] ; Ampofo, Emmanuel ^[3] ; Carpinelli, Angelo R. ^[1] ; Roma, Leticia P. ^[2] ; Ortis, Fernanda ^[4]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05508000 Sao Paulo - Brazil

^[2] Saarland Univ, Ctr Human & Mol Biol ZHMB, Dept Biophys, D-66424 Homburg - Germany

^[3] Saarland Univ, Inst Clin & Expt Surg, D-66424 Homburg - Germany

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, BR-05508000 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ANTIOXIDANTS; v. 10, n. 8 AUG 2021.
• Citações Web of Science: 0

Resumo

In type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in beta-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-2(center dot-) 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 beta-cells' function and survival during insulitis, NOX2 might be a potential target for designing therapies against early beta-cell dysfunction in the context of T1D onset. (AU)

• Processo FAPESP: 17/26339-5 - Envolvimento de isoformas da NADPH oxidase na disfunção de células secretoras de insulina expostas a citocinas pró-inflamatórias
• Beneficiário: Angelo Rafael Carpinelli
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 20/06184-0 - Caracterização da expressão de isoformas da NADPH oxidase na célula beta pancreática e sua modulação por citocinas pró-inflamatórias
• Beneficiário: Angelo Rafael Carpinelli
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/04580-2 - Estudo da destruição de células beta pancreáticas: o papel de NF-kB, HNF4a e IL6 no desenvolvimento do Diabetes mellitus
• Beneficiário: Fernanda Ortis
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/08769-1 - Papel da NAD(P)H oxidase nos mecanismos moleculares da fisiologia e patologia das células secretoras de insulina
• Beneficiário: Angelo Rafael Carpinelli
• Modalidade de apoio: Auxílio à Pesquisa - Temático