NADPH oxidase 4 in mouse β cells participates in inflammation on chronic nutrient overload

0582386 - FGÚ 2025 RIV US eng J - Journal Article
Holendová, Blanka - Benáková, Štěpánka - Křivonosková, Monika - Pavluch, Vojtěch - Tauber, Jan - Gabrielová, E. - Ježek, Petr - Plecitá-Hlavatá, Lydie
NADPH oxidase 4 in mouse β cells participates in inflammation on chronic nutrient overload.
Obesity. Roč. 32, č. 2 (2024), s. 339-351. ISSN 1930-7381. E-ISSN 1930-739X
R&D Projects: GA ČR(CZ) GA21-01205S; GA ČR(CZ) GA22-11439S; GA MŠMT(CZ) LX22NPO5104
Research Infrastructure: CCP II - 90126
Institutional support: RVO:67985823
Keywords : beta-cells * inflammation * interleukin-1 * IL-1
OECD category: Endocrinology and metabolism (including diabetes, hormones)
Impact factor: 6.9, year: 2022
Method of publishing: Open access
https://doi.org/10.1002/oby.23956

Objective:By exposing mice carrying a deletion of NADPH oxidase isoform 4, NOX4, specifically in pancreatic β cells (βNOX4−/−) to nutrient excess stimulated by a high-fat diet (HFD), this study aimed to elucidate the role of β-cell redox status in the development of meta-inflammation within the diabetic phenotype.Methods:The authors performed basic phenotyping of βNOX4−/− mice on HFD involving insulin and glycemic analyses, histochemistry of adipocytes, indirect calorimetry, and cytokine analyses. To characterize local inflammation, the study used caspase-1 activity assay, interleukin-1β immunochemistry, and real-time polymerase chain reaction during coculturing of β cells with macrophages.Results:The phenotype of βNOX4−/− mice on HFD was not associated with hyperinsulinemia and hyperglycemia but showed accumulation of excessive lipids in epididymal fat and β cells. Surprisingly, mice showed significantly reduced systemic inflammation. Decreased interleukin-1β protein levels and downregulated NLRP3-inflammasome activity were observed on chronic glucose overload in βNOX4−/− isolated islets and NOX4-silenced INS1-E cells resulting in attenuated proinflammatory polarization of macrophages/monocytes in vitro and in situ and reduced local islet inflammation.Conclusions:Experimental evidence suggests that NOX4 pro-oxidant activity in β cells is involved in NLRP3-inflammasome activation during chronic nutrient overload and participates in local inflammatory signaling and perhaps toward peripheral tissues, contributing to a diabetic inflammatory phenotype.
Permanent Link: https://hdl.handle.net/11104/0351173