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FXR protects against neonatal sepsis by enhancing the immunosuppressive function of MDSCs

Cellular & Molecular Immunology volume 22, pages 661–673 (2025)Cite this article

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A Comment to this article was published on 29 August 2025

Abstract

Myeloid-derived suppressor cells (MDSCs) play a protective role against neonatal inflammation during the early postnatal period. However, the mechanisms regulating neonatal MDSC function remain to be fully elucidated. In this study, we report that the bile acid receptor farnesoid X receptor (FXR) acts as a positive regulator of neonatal MDSC function. The FDA-approved FXR agonist obeticholic acid (OCA) protects against neonatal sepsis in an FXR-dependent manner. Genetic deficiency of FXR impairs the immunosuppressive and antibacterial functions of MDSCs, thereby exacerbating the severity of neonatal sepsis. Adoptive transfer of MDSCs alleviates sepsis in both Fxr−/− and Fxrfl/flMrp8-Cre+ pups. Mechanistic studies revealed that Hif1α, a well-established regulator of MDSCs, is a direct transcriptional target of FXR. In patients with neonatal sepsis, downregulation of FXR and HIF-1α in MDSCs was observed, which was inversely correlated with clinical parameters. These observations demonstrate the importance of FXR in neonatal MDSC function and its therapeutic potential in neonatal sepsis.

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Acknowledgements

This work was supported by the following grants: National Natural Science Foundation of China (No. 82430055, 81925018, and 82130049 to J. Z.; 82001691 to J.H.; and 82488301, 82225015, and 82171284 to Q.L.). This work was also supported by grants to J.H.; the China Postdoctoral Science Foundation (2020M672582); the Science and Technology Planning Project of Guangzhou (No. 2024A03J1237); and the New Cornerstone Science Foundation through the XPLORER PRIZE (to Q.L.).

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  1. These authors contributed equally: Juan He, Yuxin Zhang, Yuchao Jing.

Authors and Affiliations

  1. Laboratory of Immunity, Inflammation & Cancer, Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Juan He, Xiaoqing Zheng & Jie Zhou

  2. Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

    Juan He, Yuxin Zhang, Yuchao Jing, Rui Dong, Tongyang Li, Pan Zhou & Jie Zhou

  3. Guangdong Provincial Key Laboratory of Research in Structure Birth Defect Disease and Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, China

    Juan He & Wei Zhong

  4. Department of Immunology, Basic Medical College, Changzhi Medical College, Changzhi, 046000, China

    Yuchao Jing

  5. Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, China

    Kun Shi

  6. Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300050, China

    Qiang Liu

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Contributions

J. H., and Y. Z. performed the experiments, analyzed the data, and participated in figure organization and manuscript writing; Y. J., and R. D. participated in most of the experiments. T. L., X. Z. and P. Z. participated in mouse breeding and mouse model construction; K. S. and W. Z. participated in the experiments related to clinical samples; and Q. L. cosupervised this study. J. Z. conceptualized, supervised, and interpreted the experiments and wrote the manuscript with input from all the authors.

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Correspondence to Jie Zhou.

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He, J., Zhang, Y., Jing, Y. et al. FXR protects against neonatal sepsis by enhancing the immunosuppressive function of MDSCs. Cell Mol Immunol 22, 661–673 (2025). https://doi.org/10.1038/s41423-025-01289-4

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