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  • Basic Science Article
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Kawasaki disease: ubiquitin-specific protease 5 promotes endothelial inflammation via TNFα-mediated signaling

Pediatric Research volume 93, pages 1883–1890 (2023)Cite this article

Abstract

Background

This study aimed to explore the functions of ubiquitin-specific protease 5 (USP5) in the endothelial inflammation of Kawasaki disease (KD).

Methods

USP5 expression levels in HCAECs were examined after stimulation with TNFα or KD sera. The inflammatory cytokine expression level and nuclear factor κB (NF-κB) signaling activation proteins were also investigated in HCAECs by using USP5 overexpression/knockdown lentivirus as well as its small molecule inhibitor vialinin A.

Results

USP5 expression level is upregulated in HCAECs after stimulation with KD sera. Similarly, the USP5 expression level is also increased in a time- and dose-dependent manner upon TNFα stimulation in HCAECs. Moreover, USP5 sustains proinflammatory cytokine production and NF-κB signaling activation, whereas USP5 knockdown causes the proinflammatory cytokine levels to decrease and suppress NF-κB signaling activation. Notably, the USP5 inhibitor vialinin A can suppress the expression of inflammatory genes induced by TNFα and IL-1β in HCAECs.

Conclusions

Our study identified USP5 as a positive regulator of TNFα production and its downstream signaling activation during the inflammatory responses in HCAECs, and demonstrated that its inhibitor vialinin A might serve as a candidate drug for KD therapy to prevent the excessive production of proinflammatory cytokines.

Impact

  • USP5 is upregulated in human coronary artery endothelial cells (HCAECs) whether incubated with acute KD sera or TNFα in vitro.

  • USP5 promotes proinflammatory cytokine expression by sustaining NF-κB signaling activation in HCAECs.

  • The USP5 inhibitor vialinin A can suppress the expression levels of proinflammatory cytokines in HCAEC, thus providing a novel mechanism and intervention strategy in KD therapy.

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Fig. 1: USP5 expression levels are increased in HCAECs treated with KD sera or TNFα.
Fig. 2: Overexpression and knockdown of USP5 by lentivirus in HCAEC.
Fig. 3: USP5 promotes IL-8 gene transcription in TNFα-treated HCAECs.
Fig. 4: USP5 promotes NF-κB signaling activation in TNFα-treated HCAECs.
Fig. 5: Effect of vialinin A on cytokine production in HCAECs.

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Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Acknowledgements

The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.

Funding

This project was funded by the National Natural Science Foundation of China (No. 82171797, No. 81971477, No. 81870365, No. 82070512, No. 81970436, No. 81900450), Jiangsu Provincial Social Development Project (SBE2021750252), Jiangsu Provincial Medical Young Talents (QNRC2016756), the Applied Foundational Research of Medical and Health Care of Suzhou City (SYS2019086, SYS2019083, KJXW2018021), Gusu Health Talent Program (GSWS2020038), and Natural Science Foundation for Youth of Wannan Medical College (WK2021F64).

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Author notes

  1. These authors contributed equally: Chengcheng Huang, Wang Wang, Hongbiao Huang.

Authors and Affiliations

  1. Institute of Pediatric Research, Children’s Hospital of Soochow University, 215025, Suzhou, Jiangsu, China

    Chengcheng Huang, Hongbiao Huang, Jiaqi Jiang, Xiangqiang Pu, Guanghui Qian & Haitao Lv

  2. Department of Pediatric, Yijishan Hospital, Wannan Medical College, 241001, Wuhu, Anhui, China

    Chengcheng Huang

  3. School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, 215123, Suzhou, Jiangsu, China

    Wang Wang

  4. Department of Cardiology, Children’s Hospital of Soochow University, 215025, Suzhou, Jiangsu, China

    Wang Wang, Yueyue Ding, Xuan Li, Jin Ma, Miao Hou & Haitao Lv

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  1. Chengcheng Huang
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Contributions

H.L. and G.Q. conceived the study and drafted the manuscript. C.H., W.W., H.H., J.J., Y.D., X.L., M.H., J.M., and X.P. conducted the experiments, analyzed the data, and participated in the discussion. All authors read and approved the final draft.

Corresponding authors

Correspondence to Guanghui Qian or Haitao Lv.

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Huang, C., Wang, W., Huang, H. et al. Kawasaki disease: ubiquitin-specific protease 5 promotes endothelial inflammation via TNFα-mediated signaling. Pediatr Res 93, 1883–1890 (2023). https://doi.org/10.1038/s41390-022-02341-z

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