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USP10 regulates macrophage inflammation responses via stabilizing NEMO in LPS-induced sepsis

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Abstract

Background

Sepsis is a systemic inflammatory response syndrome characterized by persistent inflammation and immunosuppression, leading to septic shock and multiple organ dysfunctions. Ubiquitin-specific peptidase 10 (USP10), a deubiquitinase enzyme, plays a vital role in cancer and arterial restenosis, but its involvement in sepsis is unknown.

Objective

In this study, we investigated the significance of USP10 in lipopolysaccharide (LPS)-stimulated macrophages and its biological roles in LPS-induced sepsis.

Methods

Lipopolysaccharides (LPS) were used to establish sepsis models in vivo and in vitro. We use western blot to identify USP10 expression in macrophages. Spautin-1 and USP10-siRNA were utilized for USP10 inhibition. ELISA assays were used to assess for TNF‐α and IL-6 in vitro and in vivo. Nuclear and cytoplasmic protein extraction and Confocal microscopy were applied to verify the translocation of NF‐κB. Mechanically, co-immunoprecipitation and rescue experiments were used to validate the regulation of USP10 and NEMO.

Results

In macrophages, we found that LPS induced USP10 upregulation. The inhibition or knockdown of USP10 reduced the pro‐inflammatory cytokines TNF-α and IL-6 and suppressed LPS‐induced NF‐κB activation by regulating the translocation of NF‐κB. Furthermore, we found that NEMO, the regulatory subunit NF-κB essential modulator, was essential for the regulation of LPS-induced inflammation by USP10 in macrophages. NEMO protein evidently interacted with USP10, whereby USP10 inhibition accelerated the degradation of NEMO. Suppressing USP10 significantly attenuated inflammatory responses and improved the survival rate in LPS-induced sepsis mice.

Conclusions

Overall, USP10 was shown to regulate inflammatory responses by stabilizing the NEMO protein, which may be a potential therapeutic target for sepsis-induced lung injury.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The study was supported by the National Natural Science Foundation for Young Scientists of China (82000410); the Key Medical Disciplines and Specialties Program of Guangzhou(2021-2023); the Medical Scientific Research Foundation of Guangdong Province (A2022049); the Science and Technology Program of Meizhou (2019B0202001, 2021B0204002); the Social Development Science and Technology Program Project of Meizhou (2022B01); the Scientific Research and Cultivation Project of Meizhou People’s Hospital (PY-C2021047).

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Author notes

  1. Xiaoyan Tang, Ruiqiang Weng and Guixian Guo have contributed equally to this work.

Authors and Affiliations

  1. Medical Research and Experimental Center, Meizhou People’s Hospital, No.63 Huangtang Road, Meijiang District, Meizhou, 514031, Guangdong, China

    Xiaoyan Tang, Ruiqiang Weng, Guixian Guo, Xueqiang Wu, Sudong Liu & Zhixiong Zhong

  2. Department of Emergency, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China

    Juexian Wei & Xiaohui Chen

  3. Department of Emergency, Meizhou People’s Hospital, Meizhou, 514031, Guangdong, China

    Bin Chen

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Contributions

ZXZ and XHC designed the experiments. XYT, RQW, GXG, XQW, JXW and SDL performed the experiments and analyzed the data. XYT, ZXZ and XHC wrote the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Zhixiong Zhong or Xiaohui Chen.

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Tang, X., Weng, R., Guo, G. et al. USP10 regulates macrophage inflammation responses via stabilizing NEMO in LPS-induced sepsis. Inflamm. Res. 72, 1621–1632 (2023). https://doi.org/10.1007/s00011-023-01768-2

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  • DOI: https://doi.org/10.1007/s00011-023-01768-2

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