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Atranorin inhibits NLRP3 inflammasome activation by targeting ASC and protects NLRP3 inflammasome-driven diseases

Acta Pharmacologica Sinica volume 44, pages 1687–1700 (2023)Cite this article

Abstract

Aberrant NLRP3 activation has been implicated in the pathogenesis of numerous inflammation-associated diseases. However, no small molecular inhibitor that directly targets NLRP3 inflammasome has been approved so far. In this study, we show that Atranorin (C19H18O8), the secondary metabolites of lichen family, effectively prevents NLRP3 inflammasome activation in macrophages and dendritic cells. Mechanistically, Atranorin inhibits NLRP3 activation induced cytokine secretion and cell pyroptosis through binding to ASC protein directly and therefore restraining ASC oligomerization. The pharmacological effect of Atranorin is evaluated in NLRP3 inflammasome-driven disease models. Atranorin lowers serum IL-1β and IL-18 levels in LPS induced mice acute inflammation model. Also, Atranorin protects against MSU crystal induced mice gouty arthritis model and lowers ankle IL-1β level. Moreover, Atranorin ameliorates intestinal inflammation and epithelial barrier dysfunction in DSS induced mice ulcerative colitis and inhibits NLRP3 inflammasome activation in colon. Altogether, our study identifies Atranorin as a novel NLRP3 inhibitor that targets ASC protein and highlights the potential therapeutic effects of Atranorin in NLRP3 inflammasome-driven diseases including acute inflammation, gouty arthritis and ulcerative colitis.

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Fig. 1: Atranorin inhibits the activation of NLRP3 inflammasome in BMDM.
Fig. 2: Atranorin inhibits the activation of NLRP3 inflammasome in BMDC and NLRP3 inflammasome-reconstituted HEK293T cells.
Fig. 3: Atranorin inhibits the assembly of NLRP3 inflammasome complex through binding to ASC.
Fig. 4: Atranorin inhibits NLRP3 inflammation activation in LPS induced mice acute inflammation and MSU crystal induced mice gouty arthritis.
Fig. 5: Atranorin alleviates DSS induced mice ulcerative colitis.
Fig. 6: Atranorin inhibits NLRP3 inflammasome activation in DSS induced mice ulcerative colitis.
Fig. 7: Atranorin inhibits NLRP3 inflammasome activation by targeting ASC and protects against NLRP3 inflammasome-driven diseases.

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Acknowledgements

This work was supported by the grants of National Natural Science Foundation of China (NSFC) (No. 82173823). We thank Professor Wei-min Zhao for providing Atranorin, Bing Wu, Fang Bai, Meng-meng Xu and Hao Li for their kind assistance to this study.

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Authors and Affiliations

  1. University of Chinese Academy of Sciences, Beijing, 100049, China

    Hao-yu Wang, Shu-yue Lei & Wei Tang

  2. Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Hao-yu Wang, Guan-gen Huang, Rong Zhou, Shu-yue Lei, Jing Ren, Kai-rong Zhang, Chun-lan Feng, Yan-wei Wu & Wei Tang

  3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Xi Lin, Guan-gen Huang, Jing Ren & Wei Tang

  4. School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, China

    Kai-rong Zhang

  5. School of Medicine, Shanghai University, Shanghai, 200444, China

    Yan-wei Wu

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  1. Hao-yu Wang
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Contributions

HYW: Conceptualization, Investigation, Methodology, Formal analysis, Writing - original draft. XL: Investigation, Validation, Formal analysis. GGH: Investigation, Validation. RZ: Investigation, Formal analysis. SYL: Investigation. JR: Investigation. KRZ: Investigation. CLF: Resources, Data curation. YWW: Conceptualization, Funding acquisition, Supervision, Writing - review & editing. WT: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Resources, Writing - review & editing.

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Correspondence to Yan-wei Wu or Wei Tang.

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Wang, Hy., Lin, X., Huang, Gg. et al. Atranorin inhibits NLRP3 inflammasome activation by targeting ASC and protects NLRP3 inflammasome-driven diseases. Acta Pharmacol Sin 44, 1687–1700 (2023). https://doi.org/10.1038/s41401-023-01054-1

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