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Oridonin attenuates carrageenan-induced pleurisy via activation of the KEAP-1/Nrf2 pathway and inhibition of the TXNIP/NLRP3 and NF-κB pathway in mice

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Abstract

The classic NLRP3 inflammasome and NF-κB molecular pathways are activated in many inflammatory-related diseases, such as pleurisy. Because oridonin (Ori) has been indicated as a covalent NLRP3 inhibitor with strong anti-inflammasome activity, we herein aimed to assess the effects of Ori in a mouse model of carrageenan (CAR)-induced pleurisy. The results showed that CAR caused hemorrhaging and exudation of lung tissues and the release of inflammatory factors (TNF-α, IL-6 and IL-1β), effects that were significantly reduced by treatment with Ori. In addition, increased neutrophil infiltration, protein concentrations and volumes were found in the exudates of the CAR group, and these phenomena were suppressed by Ori treatment. Regarding cellular pathways, Ori could alleviate the CAR-activated NF-κB and TXNIP/NLRP3 pathways. Additionally, oxidative stress was shown to be involved in the pathogenesis of pleurisy, but possible mechanisms remain to be explored. Herein, Ori reversed the CAR-induced depletion of GSH and SOD and the CAR-induced increases in ROS, MPO and MDA levels. Furthermore, Ori inhibited NOX-4 levels, initiated the dissociation of KEAP-1 from Nrf2, activated the downstream genes HO-1 and exerted antioxidative effects on CAR-induced pleurisy. In conclusion, Ori conferred protection against CAR-induced pleurisy via Nrf2-dependent antioxidative and NLRP3-dependent anti-inflammatory properties.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81870030) and the General Financial Grant from the China Postdoctoral Science Foundation (Grant No. 2018T110257).

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Author notes

  1. Huahong Yang, Jingbo Huang, Zhongmei Wen, Liping Peng and Xinxin Ci have contributed equally to this paper.

Authors and Affiliations

  1. Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China

    Huahong Yang, Jingbo Huang & Xinxin Ci

  2. Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, China

    Huahong Yang, Zhongmei Wen & Liping Peng

  3. Department of Pediatric Ultrasound, The First Hospital of Jilin University, Changchun, 130061, China

    Yanli Gao

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  1. Huahong Yang
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  2. Jingbo Huang
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  3. Yanli Gao
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  4. Zhongmei Wen
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  5. Liping Peng
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Correspondence to Liping Peng or Xinxin Ci.

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Yang, H., Huang, J., Gao, Y. et al. Oridonin attenuates carrageenan-induced pleurisy via activation of the KEAP-1/Nrf2 pathway and inhibition of the TXNIP/NLRP3 and NF-κB pathway in mice. Inflammopharmacol 28, 513–523 (2020). https://doi.org/10.1007/s10787-019-00644-y

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