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Theaflavin mitigates acute gouty peritonitis and septic organ injury in mice by suppressing NLRP3 inflammasome assembly

Acta Pharmacologica Sinica volume 44, pages 2019–2036 (2023)Cite this article

Abstract

Activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays important role in defending against infections, but its aberrant activation is causally linked to many inflammatory diseases, thus being a therapeutic target for these diseases. Theaflavin, one major ingredient of black tea, exhibits potent anti-inflammatory and anti-oxidative activities. In this study, we investigated the therapeutic effects of theaflavin against NLRP3 inflammasome activation in macrophages in vitro and in animal models of related diseases. We showed that theaflavin (50, 100, 200 μM) dose-dependently inhibited NLRP3 inflammasome activation in LPS-primed macrophages stimulated with ATP, nigericin or monosodium urate crystals (MSU), evidenced by reduced release of caspase-1p10 and mature interleukin-1β (IL-1β). Theaflavin treatment also inhibited pyroptosis as shown by decreased generation of N-terminal fragment of gasdermin D (GSDMD-NT) and propidium iodide incorporation. Consistent with these, theaflavin treatment suppressed ASC speck formation and oligomerization in macrophages stimulated with ATP or nigericin, suggesting reduced inflammasome assembly. We revealed that theaflavin-induced inhibition on NLRP3 inflammasome assembly and pyroptosis resulted from ameliorated mitochondrial dysfunction and reduced mitochondrial ROS production, thereby suppressing interaction between NLRP3 and NEK7 downstream of ROS. Moreover, we showed that oral administration of theaflavin significantly attenuated MSU-induced mouse peritonitis and improved the survival of mice with bacterial sepsis. Consistently, theaflavin administration significantly reduced serum levels of inflammatory cytokines including IL-1β and attenuated liver inflammation and renal injury of mice with sepsis, concomitant with reduced generation of caspase-1p10 and GSDMD-NT in the liver and kidney. Together, we demonstrate that theaflavin suppresses NLRP3 inflammasome activation and pyroptosis by protecting mitochondrial function, thus mitigating acute gouty peritonitis and bacterial sepsis in mice, highlighting a potential application in treating NLRP3 inflammasome-related diseases.

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Fig. 1: Theaflavin inhibits ATP- or nigericin-induced NLRP3 inflammasome activation in macrophages.
Fig. 2: Theaflavin blocks ASC speck formation and oligomerization upon NLRP3 activation.
Fig. 3: Theaflavin suppresses pyroptosis by inhibiting GSDMD-NT generation.
Fig. 4: Theaflavin alleviates mitochondrial damage induced by ATP or nigericin.
Fig. 5: Theaflavin inhibits ROS production induced by ATP or nigericin.
Fig. 6: Theaflavin inhibits NEK7-NLRP3 interaction during ATP- or nigericin-induced NLRP3 inflammasome activation.
Fig. 7: Theaflavin inhibits NLRP3 inflammasome assembly and necrosis in macrophages treated with MSU.
Fig. 8: MSU-induced peritonitis is alleviated by theaflavin treatment.
Fig. 9: Theaflavin alleviates sepsis in mice.
Fig. 10: Theaflavin protects against septic shock organ injury in mice.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82274167, 81873064, and 81773965) and by Funding of Science and Technology Projects in Guangzhou (202201020083). We also thank Prof. Yong-tang Zheng (Kunming Institute of Zoology, Chinese Academy of Sciences) for his kind help in this study.

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  1. These authors contributed equally: Si-yuan Chen, Ya-ping Li, Yi-ping You

Authors and Affiliations

  1. Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China

    Si-yuan Chen, Ya-ping Li, Yi-ping You, Hong-rui Zhang, Qi-qi Liang, Tao Yuan, Rong Xu, Dong-yun Ou-Yang & Xian-hui He

  2. Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China

    Zi-jian Shi & Qing-bing Zha

  3. Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China

    Li-hui Xu

  4. Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China

    Qing-bing Zha & Xian-hui He

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  1. Si-yuan Chen
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Contributions

XHH, DYOY, and QBZ conceived and supervised the research; SYC, YPL, YPY, and HRZ performed in vitro experiments; ZJS, QQL, TY, RX, and LHX performed animal experiments; SYC and XHH analyzed the data; XHH, DYOY, and SYC wrote the paper.

Corresponding authors

Correspondence to Qing-bing Zha, Dong-yun Ou-Yang or Xian-hui He.

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Chen, Sy., Li, Yp., You, Yp. et al. Theaflavin mitigates acute gouty peritonitis and septic organ injury in mice by suppressing NLRP3 inflammasome assembly. Acta Pharmacol Sin 44, 2019–2036 (2023). https://doi.org/10.1038/s41401-023-01105-7

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