NRF2 is a spatiotemporal metabolic hub driving the polyfunctionality of Th2 cells in allergic asthma
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ABSTRACT:
PROVIDER: PRJNA1006633 | ENA |
REPOSITORIES: ENA
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Project description:Polyfunctional T cell responses are detrimental in immune disorders; however, it is unclear how effector T cell subsets acquire polyfunctionality in tissues. Here, we demonstrate that the activation of Nrf2 is necessary for the differentiation polyfunctional Th2 cells in vivo. Reactive oxygen species (ROS) levels are significantly elevated in lung-infiltrating immune cells during allergic asthma, and inhibiting either ROS or Nrf2 significantly decreases eosinophilia and polyfunctional Th2 cells in the lung. In vivo studies using multiple cell-type specific Nrf2-deficient mice and mixed bone marrow chimeras revealed that cell-intrinsic Nrf2 drives IL-5 and IL-13 expression in Th2 cells independently of IL-33. Mechanistically, Nrf2 promotes optimal OXPHOS and glycolysis capacity by inducing PPARg expression and glucose uptake to drive polyfunctionality of Th2 cells. Blocking Nrf2 reduces IL-5 and IL-13 production from house dust mite allergen-specific Th2 cells obtained from asthma patients. These findings demonstrate that Nrf2 acts as a spatiotemporal metabolic hub driving the differentiation of polyfunctional Th2 cells, which may have therapeutic implications for controlling allergic lung inflammation.
2023-08-24 | GSE241138 | GEO
Project description:Polyfunctional Th2 cells play a crucial role in triggering diverse pathogenic responses in allergic diseases by producing multiple cytokines. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of Nrf2 in polyfunctional Th2 cells during allergic asthma. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma. Deletion of the ROS sensor Nrf2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, Nrf2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality, partially by inducing PPARγ, independently of IL-33. Treatment with an Nrf2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice, and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells (PBMCs) in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases.
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Project description:NRF2 is a spatiotemporal metabolic hub driving the polyfunctionality of Th2 cells in allergic asthma
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