
Nox2 in regulatory T cells promotes angiotensin II-induced cardiovascular remodeling.
The Journal of clinical investigation
The superoxide-generating enzyme Nox2 contributes to hypertension and cardiovascular remodeling triggered by activation of the renin-angiotensin system. Multiple Nox2-expressing cells are implicated in angiotensin II-induced (Ang II-induced) pathophysiology, but the importance of Nox2 in leukocyte subsets is poorly understood. Here, we investigated the role of Nox2 in T cells, particularly Tregs. Mice globally deficient in Nox2 displayed increased numbers of Tregs in the heart at baseline, whereas Ang II-induced effector T cell (Teff) infiltration was inhibited. To investigate the role of Treg Nox2, we generated a mouse line with CD4-targeted Nox2 deficiency (Nox2fl/flCD4Cre+). These animals showed inhibition of Ang II-induced hypertension and cardiac remodeling related to increased tissue-resident Tregs and reduction in infiltrating Teffs, including Th17 cells. The protection in Nox2fl/flCD4Cre+ mice was reversed by anti-CD25 antibody depletion of Tregs. Mechanistically, Nox2-/y Tregs showed higher in vitro suppression of Teff proliferation than WT Tregs, increased nuclear levels of FoxP3 and NF-κB, and enhanced transcription of CD25, CD39, and CD73. Adoptive transfer of Tregs confirmed that Nox2-deficient cells had greater inhibitory effects on Ang II-induced heart remodeling than WT cells. These results identify a previously unrecognized role of Nox2 in modulating suppression of Tregs, which acts to enhance hypertension and cardiac remodeling.
10.1172/JCI97490
NOX2 deficiency promotes GSDME-related pyroptosis by reducing AMPK activation in neutrophils.
International immunopharmacology
Nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2) is an effector molecule expressed predominantly in neutrophils. Its deficiency is present in immune disorders, including systemic lupus erythematosus, chronic granulomatous disease, and rheumatoid arthritis. Recent reports indicated that NOX2 regulates autoimmunity and programmed cell death. However, the exact mechanism is unclear. In this study, we explored the effect of NOX2 on neutrophil apoptosis. We demonstrated that NOX2 deficiency caused neutrophil pyroptosis. Mechanistically, the NOX2 inhibitor GSK2795039 application or knockdown of NOX2 components resulted in increased mitochondrial ROS, inhibition of AMP-activated protein kinase (AMPK), and activation of Gasdermin E. AMPK activators, metformin and epigallocatechin gallate, inhibited deficient NOX2-induced pyroptosis. Together, these findings illustrate the involvement of NOX2 in regulating neutrophil death and emphasize its importance in autoimmunity.
10.1016/j.intimp.2024.113504