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Essential roles of S100A10 in Toll-like receptor signaling and immunity to infection

Cellular & Molecular Immunology volume 17, pages 1053–1062 (2020)Cite this article

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Abstract

Toll-like receptors (TLRs) are key pattern recognition receptors that mediate innate immune responses to infection. However, uncontrolled TLR activation can lead to severe inflammatory disorders such as septic shock. The molecular mechanisms through which TLR responses are regulated are not fully understood. Here, we demonstrate an essential function of S100A10 in TLR signaling. S100A10 was constitutively expressed in macrophages, but was significantly downregulated upon TLR activation. S100A10-deficient macrophages were hyperresponsive to TLR stimulation, and S100A10-deficient mice were more sensitive to endotoxin-induced lethal shock and Escherichia coli-induced abdominal sepsis. Mechanistically, S100A10 regulated macrophage inflammatory responses by interfering with the appropriate recruitment and activation of the receptor-proximal signaling components and eventually inhibited TLR-triggered downstream signaling. These findings expand our understanding of TLR signaling and establish S100A10 as an essential negative regulator of TLR function and a potential therapeutic target for treating inflammatory diseases.

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Acknowledgements

This work was funded by the National Natural Science Foundation of China (Grant No. 81871309) and the Program for Ph.D. Starting Research Funding from Xinxiang Medical University (Grant No. 505248). We thank Drs. Bo Yang, Yun Zhang, Qianqian Zheng, Liangwei Duan, Chunlei Guo, Jie Wang, Zhiguo Niu, and Hui Liu for reagents and/or valuable advice. We are also grateful to Drs. Wei Zhao (Shandong University) and Peihui Wang (Shandong University) for providing plasmids and to Dr. Youhai Chen (University of Pennsylvania) for critical reading and editing of the manuscript.

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  1. These authors contributed equally: Yunwei Lou, Meijuan Han

Authors and Affiliations

  1. Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China

    Yunwei Lou, Meijuan Han, Huandi Liu, Yuna Niu, Yinming Liang & Hui Wang

  2. Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China

    Yunwei Lou, Meijuan Han, Huandi Liu, Yuna Niu, Yinming Liang, Jiqiang Guo, Wen Zhang & Hui Wang

  3. Laboratory of Genetic Regulators in the Immune System, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China

    Yinming Liang

  4. Department of Immunology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, Henan, 453000, People’s Republic of China

    Jiqiang Guo

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  1. Yunwei Lou
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Contributions

H.W. and Y.L. conceived the study and wrote the manuscript; Y.L. and M.H. performed most of the experiments and analyzed the data. H.L. performed some of the in vivo experiments. Y.N. performed the histopathology study on the lung samples. J.G. and Y.L. generated and supplied S100a10−/− mice. W.Z. provided expertise and advice. H.W. oversaw the project.

Corresponding author

Correspondence to Hui Wang.

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Lou, Y., Han, M., Liu, H. et al. Essential roles of S100A10 in Toll-like receptor signaling and immunity to infection. Cell Mol Immunol 17, 1053–1062 (2020). https://doi.org/10.1038/s41423-019-0278-1

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