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IL-33-induced reactive oxygen species are required for optimal metabolic programming in group 2 innate lymphoid cells

Cellular & Molecular Immunology volume 17, pages 1266–1268 (2020)Cite this article

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Increasing evidence indicates that airway inflammation is linked to the generation of reactive oxygen species (ROS),1 which serve as important signaling molecules for various immune cells. Antioxidant-based interventions are therefore a potential strategy for treating airway inflammation, but the therapeutic effects require improvement by precise use in the proper situations.2 Group 2 innate lymphoid cells (ILC2s) play an important role in the early phase of airway inflammation, and their activities are dependent on metabolic activation.3 However, the molecular mechanisms underlying the metabolic activation and functions of ILC2s are not fully understood. Here, we found that the ROS levels in ILC2s increased upon cellular activation both in vivo and in vitro. An ROS scavenger, N-acetyl cysteine (NAC), compromised cytokine production and the proliferation of ILC2s, as well as ILC2-mediated eosinophilia, in response to IL-33 stimulation. Mechanistically, ROS are required for optimal IL-33-triggered activation of the metabolic program and for Akt-mechanistic target of rapamycin (mTOR) signaling in ILC2s. In mouse models, NAC alleviated IL-33-triggered ILC2 activation and inflammation in vivo in the airway and the liver. Collectively, our study indicates that IL-33-induced ROS are required for the optimal metabolic activation and functions of ILC2s and suggests that antioxidant therapy might ameliorate the ILC2-mediated immune responses and inflammation in the airway, liver, and possibly other organs.

The ILC2 numbers in the lung were slightly increased in the Nox2−/− mice compared with the wild-type mice (Fig. S2b). However, after intranasal IL-33 challenge, infiltration of ILC2s into the airway was compromised in the Nox2−/− mice (Fig. S2c). In addition, significantly reduced levels of IL-5 and IL-13 and fewer eosinophils were detected in the BALF of the Nox2−/− mice than that of the wild-type mice (Fig. S2d, e). These data demonstrated that NOX2 is required for IL-33-driven airway ILC2 responses and inflammation, suggesting that IL-33-induced ROS might play a role in ILC2 functions.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2019YFA0906100 to X.W.), the Natural Science Foundation of Guangdong Province (2019A1515011412 to J.B.), the Shenzhen Technology Innovation Project (JCYJ20170413153158716 to X.W.), the Shenzhen Special Funds of Industry in the Future (Development and Reform Commission in Shenzhen [2015] 971 to X.W.), and the Special Funds for Major Science and Technology of Guangdong Province (2013A022100037 to X.W.).

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Authors and Affiliations

  1. Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China

    Chaoyue Zheng, Haisi Wu, Zhen Lu, Jiacheng Bi & Xiaochun Wan

  2. University of Chinese Academy of Sciences, Beijing, China

    Haisi Wu, Zhen Lu, Jiacheng Bi & Xiaochun Wan

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  1. Chaoyue Zheng
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  2. Haisi Wu
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Contributions

C.Z. performed the experiments, analyzed the data, and wrote the manuscript. H.W. and Z.L. provided technical assistance. J.B. conceived the research, designed the experiments, performed the experiments and transcriptome analysis, analyzed the data, and wrote the manuscript. X.W. supervised the research.

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Correspondence to Jiacheng Bi or Xiaochun Wan.

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Zheng, C., Wu, H., Lu, Z. et al. IL-33-induced reactive oxygen species are required for optimal metabolic programming in group 2 innate lymphoid cells. Cell Mol Immunol 17, 1266–1268 (2020). https://doi.org/10.1038/s41423-020-0393-z

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