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NRF2 is a spatiotemporal metabolic hub driving the polyfunctionality of Th2 cells in allergic asthma

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE241355 | GEO | 2023/08/25

REPOSITORIES: GEO

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Project description:Background: In asthma, airway epithelium remodeling can already be detected during childhood, and epithelial cells are more susceptible to virus and oxidative stress. Their exact role in natural history and severity of children allergic respiratory disease remains however surprisingly unexplored. Aim: To analyze dysfunctions of epithelium in dust mite allergic respiratory disease (rhinitis ¬± asthma) in children. Methods: Expression profilings of nasal epithelial cells collected by brushing were performed on Affymetrix Hugene 1.0 ST arrays. All allergic patients were sensitized to dust mite. 19 patients had an isolated allergic rhinitis (AR). 14 patients had AR associated with asthma. Patients were compared to 12 controls, their severity and control being assessed according to NAEPP and ARIA criteria. Infections by respiratory viruses were excluded by real-time PCR measurements. Results: 61 probes were able to distinguish allergic rhinitis children from healthy controls. A majority of these probes was under the control of Th2 cytokines, as evidenced by parallel experiments performed on primary cultures of nasal epithelial cells. In uncontrolled asthmatic patients, we observed not only an enhanced expression of these Th2-responsive transcripts, but also a down-regulation of interferon-responsive genes. Conclusion: Our study identifies a Th2 driven epithelial phenotype common to all dust mite allergic children. Besides, it suggests that epithelium is involved in the severity of the disease. Expression profiles observed in uncontrolled asthmatic patients suggest that severity of asthma is linked at the same time to atopy and to impaired viral response. Nasal epithelium gene expression profiling of dust mite allergic children with isolated rhinitis, rhinitis associated with asthma and controls. 38 samples classified in 4 categories : 14 isolated rhinitis (R), 6 rhinitis with uncontrolled asthma (UA), 7 rhinitis with controlled asthma (CA) and 11 healthy subjects (C )

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NRF2 is a spatiotemporal metabolic hub driving the polyfunctionality of Th2 cells in allergic asthma

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