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Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways

Cellular & Molecular Immunology volume 18, pages 1489–1502 (2021)Cite this article

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Abstract

Spaceflight-associated immune system weakening ultimately limits the ability of humans to expand their presence beyond the earth's orbit. A mechanistic study of microgravity-regulated immune cell function is necessary to overcome this challenge. Here, we demonstrate that both spaceflight (real) and simulated microgravity significantly reduce macrophage differentiation, decrease macrophage quantity and functional polarization, and lead to metabolic reprogramming, as demonstrated by changes in gene expression profiles. Moreover, we identified RAS/ERK/NFκB as a major microgravity-regulated pathway. Exogenous ERK and NFκB activators significantly counteracted the effect of microgravity on macrophage differentiation. In addition, microgravity also affects the p53 pathway, which we verified by RT-qPCR and Western blot. Collectively, our data reveal a new mechanism for the effects of microgravity on macrophage development and provide potential molecular targets for the prevention or treatment of macrophage differentiation deficiency in spaceflight.

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Fig. 1: Microgravity decreases the total number of cells and inhibits the differentiation of macrophages from HPCs.
Fig. 2: M1/M2 macrophage polarization is impaired after in vitro differentiation in a simulated microgravity environment.
Fig. 3: Microgravity-altered genes involved in key biological processes.
Fig. 4: Metabolic changes in response to microgravity.
Fig. 5: The major macrophage differentiation signaling pathways impacted by microgravity.
Fig. 6: Activation of RAS/ERK/NFκB signaling pathways rescues the effects of microgravity.
Fig. 7: Microgravity activates the p53 signaling pathway.

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Data availability

The raw RNA-Seq data from this study were deposited into the BIGD Genome Sequence Archive (GSA) under accession number CRA000920.

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Acknowledgements

The authors appreciate Drs. Yuzhu Hou and Peng Wang for their critical review of our manuscript. This work was supported by grants from the National Key Research and Development Program of China (2017YFA0105002, Y.Z., 2017YFA0104402, L.L.), Joint Funds of the National Natural Science Foundation of China (U1738111, Y.Z.), the China Manned Space Flight Technology Project (TZ-1), and the National Natural Science Foundation Youth Fund (31800741, L.S.).

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  1. These authors contributed equally: Lu Shi, Hongling Tian, Peng Wang, Ling Li

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Lu Shi, Hongling Tian, Peng Wang, Ling Li, Zhaoqi Zhang, Jiayu Zhang & Yong Zhao

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

    Lu Shi, Hongling Tian, Peng Wang, Ling Li, Zhaoqi Zhang, Jiayu Zhang & Yong Zhao

  3. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China

    Yong Zhao

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Contributions

Y.Z., H.T., and L.S. conceived the study and designed the experiments. L.S. analyzed and interpreted all the data and drafted the manuscript with input from all coauthors. H.T. prepared the mouse HPCs and performed the cell experiments. P.W. conducted the molecular experiments. L.L., Z.Z., and J.Z. processed the raw data from NGS. Y.Z. supervised the project and provided critical feedback at all stages.

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Correspondence to Yong Zhao.

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Shi, L., Tian, H., Wang, P. et al. Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways. Cell Mol Immunol 18, 1489–1502 (2021). https://doi.org/10.1038/s41423-019-0346-6

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