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FBXO38 regulates macrophage polarization to control the development of cancer and colitis

Cellular & Molecular Immunology volume 20, pages 1367–1378 (2023)Cite this article

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Abstract

Macrophages are highly plastic cells that differentially regulate multiple pathological conditions, including cancer and autoimmune diseases. In response to various stimuli, macrophages activate different intrinsic signaling pathways and polarize into distinct macrophage subsets. We aimed to identify key new effectors that could control macrophage polarization and impact the development of cancer or colitis. Following treatment with the supernatants of tumor cells, macrophages showed an upregulation in Fbxo38 expression. Subsequently, we further identified that FBXO38 promotes macrophage immunosuppressive function by upregulating the expression of M2-like genes via MAPK and IRF4 signaling without affecting M1-like macrophage polarization. Deletion of Fbxo38 in macrophages was found to block tumor development and protect against DSS-induced colitis. Considering the distinct regulation of tumor development by FBXO38 in T cells and macrophages, we suggest that a comprehensive understanding of FBXO38 function in different cell types is critical for its further translational usage.

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Data availability

The RNA sequencing data (GSE243182) and single-cell sequence analysis data [20, 21] (GSE125527, GSE140228) were deposited in the Gene Expression Omnibus. All other remaining data are available within the article and Supplementary Files or can be obtained from the corresponding author (HW) upon request.

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Acknowledgements

We thank Hangzhou Institute for Advanced Study and Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences. This work was supported by grants from the National Natural Science Foundation of China (81825011, 32221002, 81930038 and 82303154), the Ministry of Science and Technology of China (2018YFA0800702), the Science and Technology Commission of Shanghai Municipality (22JC1403001, HS2021SHZX001) and the China Postdoctoral Science Foundation (2022M723141).

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  1. These authors contributed equally: Xin Zheng, Qi Jiang.

Authors and Affiliations

  1. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China

    Xin Zheng, Qi Jiang, Fenfen Ye, Jialu Wang, Fajian Hou & Hongyan Wang

  2. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China

    Xin Zheng, Mingshun Han, Mingchang Wang, Ying Qiu, Minxia Gao, Fajian Hou & Hongyan Wang

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  1. Xin Zheng
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Contributions

XZ and QJ performed the majority of the experiments and analyzed the data. MH, FY, MW, YQ, JW, MG and FH helped with the experiments. XZ, QJ and HW designed the study and wrote the paper.

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Correspondence to Hongyan Wang.

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Zheng, X., Jiang, Q., Han, M. et al. FBXO38 regulates macrophage polarization to control the development of cancer and colitis. Cell Mol Immunol 20, 1367–1378 (2023). https://doi.org/10.1038/s41423-023-01081-2

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