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Role of the Nucleotide-Binding Domain-Like Receptor Protein 3 Inflammasome in the Endothelial Dysfunction of Early Sepsis

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Abstract

Endothelial dysfunction is responsible for multiple organ failure and the high mortality rate of sepsis. Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome plays an essential role in the progression of sepsis. However, the role of NLRP3 inflammasome in the endothelial dysfunction of sepsis has not been fully elucidated. In this study, septic mice were induced by cecal ligation and puncture (CLP) operation, and human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS). The 24-h survival rate after CLP was observed. Vasodilation function of the aorta was detected by vascular reactivity experiments. Expression of p-eNOS, eNOS, TLR4, MYD88, p-p65, p65, p-ikbα, ikbα, iNOS, NLRP3, and IL-1β in the aorta and HUVECs were determined by Western blot. Our results suggest that the p-eNOS expression was downregulated, the endothelium-dependent relaxation function was impaired, and TLR4, MYD88, p-p65, p-ikbα, iNOS, NLRP3, and IL-1β expression increased after CLP. The onset of death was 12 h after CLP, and the mortality rate was nearly 50% at 24 h after operation. The decline of p-eNOS, endothelium-dependent vasodilation function, and survival rate significantly improved with NLRP3-specific inhibitor MCC950 intervention or NLRP3 knockout in CLP mice. The decrease of p-eNOS in HUVECs induced by LPS was alleviated when pretreated with MCC950 or interleukin-1 receptor antagonist (IL-1Ra). In summary, our results indicate that activation of the NLRP3 inflammasome contributes to the development of endothelial dysfunction of early sepsis in mice, suggesting its potential role as a therapeutic target for the treatment of sepsis.

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Funding

This work was supported by the National Natural Science Foundation of China (81270210) and (31400999).

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Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Minghao Luo, Jiayu Meng, Dingyi Lv, Chang Li, Xiyang Yang & Suxin Luo

  2. Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China

    Minghao Luo, Jiayu Meng, Jianghong Yan, Feifei Shang, Dingyi Lv, Chang Li, Xiyang Yang & Suxin Luo

  3. School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Zhejiang, 325035, China

    Ting Zhang

  4. The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Suxin Luo

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  1. Minghao Luo
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Luo, M., Meng, J., Yan, J. et al. Role of the Nucleotide-Binding Domain-Like Receptor Protein 3 Inflammasome in the Endothelial Dysfunction of Early Sepsis. Inflammation 43, 1561–1571 (2020). https://doi.org/10.1007/s10753-020-01232-x

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