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Neutrophil–macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome

Cellular & Molecular Immunology (2024)Cite this article

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Abstract

Cytokine storm syndrome (CSS) is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies, infections, and autoimmune conditions. However, the potential interplay between innate immune cells is not fully understood. Here, using poly I:C and lipopolysaccharide (LPS)-induced cytokine storm models, a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model. Intravital imaging revealed neutrophil-derived extracellular vesicles (NDEVs) in the liver and spleen, which were captured by macrophages. NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models. Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite, itaconate, which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase (Acod1, encoded by Irg1). Irg1 in macrophages, but not in neutrophils, was critical for the NDEV-mediated anti-inflammatory effects. Mechanistically, NDEVs delivered miR-27a-3p, which suppressed the expression of Suclg1, the gene encoding the enzyme that metabolizes itaconate, thereby resulting in the accumulation of itaconate in macrophages. These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.

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Acknowledgements

This work was supported by grants from The Ministry of Science and Technology of China (2020YFC2002800 to Jing Wang) and the National Natural Science Foundation of China (82371760 to Jing Wang and 82272181 to Yan Luo). We extend our gratitude to the Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, for their assistance with the quantification of itaconate in this work.

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  1. These authors contributed equally: Haixia Kang, Ting Liu.

Authors and Affiliations

  1. Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Haixia Kang, Yuanyuan Wang, Wenjuan Bai & Jing Wang

  2. Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Ting Liu & Yan Luo

  3. Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jing Wang

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  1. Haixia Kang
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Contributions

H-XK performed most of the experiments, analyzed the data, and interpreted the data. TL contributed to the in vitro assay. Y-YW and W-JB provided technique support. JW and YL designed and supervised the study. H-XK and JW wrote the manuscript.

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Correspondence to Yan Luo or Jing Wang.

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Kang, H., Liu, T., Wang, Y. et al. Neutrophil–macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01174-6

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