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Restoration of the Mucosal IgA Response by Improving CD4+ T Pyroptosis Fails to Attenuate Gut Bacterial Translocation and Organ Damage After LPS Attack

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Abstract

Background

Currently, the mechanisms of impaired gut mucosal immunity in sepsis remain unclear. Gut immunoglobulin A (IgA) is an important defense mechanism against invasive pathogens, and CD4+ T cells regulate the IgA response.

Aim

We aimed to verify the hypothesis indicating that CD4+ T pyroptosis induced by lipopolysaccharide (LPS) leads to an impaired gut IgA response and subsequent bacterial translocation and organ damage.

Methods

Cultured CD4+ T cells and mice were manipulated with LPS, and pyroptosis was improved by A438079 or adoptive CD4+ T cell transfer. The changes demonstrated in pyroptosis-related molecules, cytotoxicity and CD4+ T cells were examined to determine CD4+ T pyroptosis. The changes demonstrated in IgA+ B cells, AID (key enzyme for immunoglobulins) and IgA production and function were examined to evaluate the IgA response. Serum biomarkers, bacterial colonies and survival analysis were detected for bacterial translocation and organ damage.

Results

LPS attack induced CD4+ T pyroptosis, as evidenced by increased expression of P2X7, Caspase-11 and cleaved GSDMD, which elevated cytotoxicity and decreased CD4+ T cells. Decreased CD4+ T subsets (Foxp3+ T and Tfh cells) influenced the IgA response, as evidenced by lower AID expression, which decreased IgA+ B cells and IgA production and function. A438079 or cell transfer improved the IgA response but failed to reduce the translocation of gut pathogens, damage to the liver and kidney, and mortality of mice.

Conclusion

LPS attack results in CD4+ T pyroptosis. Improvement of pyroptosis restores the mucosal IgA response but fails to ameliorate bacterial translocation and organ damage.

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Acknowledgments

The authors thank Dr. Yu-zhuang Li and Ying-shi chen (Zhongshan School of Medicine, Sun Yat-sen University) for their professional advice in Flow cytometry. Reprints will not be available from the authors.

Funding

This work was supported by grants from Natural Science Foundation of Guangdong Province, China (No. 2021A1515010990 to Xu-yu Zhang). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. Zi-Meng Liu, Yi-nan Zhang, and Hu-fei Zhang have contributed equally to this study.

Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510089, China

    Yi-nan Zhang, Hu-fei Zhang, Xiao-jun Chen, Hui Peng & Xu-Yu Zhang

  2. Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China

    Zi-Meng Liu

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  1. Zi-Meng Liu
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Contributions

All authors contributed to the study conception and design. Material preparation, cultured cell and animal experiments, data collection and analysis were performed by Z-ML, YZ, HZ, XC, HP and XZ. The first draft of the manuscript was written by Z-ML and XZ, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xu-Yu Zhang.

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Liu, ZM., Zhang, Yn., Zhang, Hf. et al. Restoration of the Mucosal IgA Response by Improving CD4+ T Pyroptosis Fails to Attenuate Gut Bacterial Translocation and Organ Damage After LPS Attack. Dig Dis Sci 69, 798–810 (2024). https://doi.org/10.1007/s10620-024-08278-z

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  • DOI: https://doi.org/10.1007/s10620-024-08278-z

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