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Synthetic vitamin K analogs inhibit inflammation by targeting the NLRP3 inflammasome

Cellular & Molecular Immunology volume 18, pages 2422–2430 (2021)Cite this article

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Abstract

Vitamin K refers to a group of structurally similar vitamins that are essential for proper blood coagulation, as well as bone and cardiovascular health. Previous studies have indicated that vitamin K may also have anti-inflammatory properties, although the underlying mechanisms of its anti-inflammatory effects remain unclear. The NLRP3 inflammasome is a multiprotein complex, and its activation leads to IL-1β and IL-18 secretion and contributes to the pathogenesis of various human inflammatory diseases. Here, we show that synthetic vitamins K3 and K4 are selective, potent inhibitors of the NLRP3 inflammasome and specifically block the interaction between NLRP3 and ASC, thereby inhibiting NLRP3 inflammasome assembly. Moreover, we show that treatment with vitamin K3 or K4 attenuates the severity of inflammation in a mouse model of peritonitis. Our results demonstrate that vitamins K3 and K4 exert their anti-inflammatory effects by inhibiting NLRP3 inflammasome activation and indicate that vitamin K supplementation may be a treatment option for NLRP3-associated inflammatory diseases.

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References

  1. Ivanova, D. et al. Vitamin K: Redox-modulation, prevention of mitochondrial dysfunction and anticancer effect. Redox Biol. 16, 352–358 (2018).

    Article  CAS  Google Scholar 

  2. DiNicolantonio, J. J., Bhutani, J. & O’Keefe, J. H. The health benefits of vitamin K. Open Heart 2, e000300 (2015).

    Article  Google Scholar 

  3. Thijssen, H. H., Vervoort, L. M., Schurgers, L. J. & Shearer, M. J. Menadione is a metabolite of oral vitamin K. Br. J. Nutr. 95, 260–266 (2006).

    Article  CAS  Google Scholar 

  4. Hirota, Y. et al. Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats. J. Biol. Chem. 288, 33071–33080 (2013).

    Article  CAS  Google Scholar 

  5. Thijssen, H. H. & Drittij-Reijnders, M. J. Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4. Br. J. Nutr. 72, 415–425 (1994).

    Article  CAS  Google Scholar 

  6. Rosati, M. Saunders handbook of veterinary drugs: small and large animals. Can. Vet. J. 58, 728 (2017).

    PubMed Central  Google Scholar 

  7. Wen, L., Chen, J., Duan, L. & Li, S. Vitamin Kdependent proteins involved in bone and cardiovascular health (Review). Mol. Med. Rep. 18, 3–15 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Li, Y., Chen, J. P., Duan, L. & Li, S. Effect of vitamin K2 on type 2 diabetes mellitus: a review. Diabetes Res. Clin. Pract. 136, 39–51 (2018).

    Article  CAS  Google Scholar 

  9. Nowak, J. K. et al. Prevalence and correlates of vitamin K deficiency in children with inflammatory bowel disease. Sci. Rep. 4, 4768 (2014).

    Article  Google Scholar 

  10. Cozzolino, M. et al. Vitamin K in chronic kidney disease. Nutrients 11, 168 (2019).

    Article  CAS  Google Scholar 

  11. Ohsaki, Y. et al. Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor kappaB through the repression of IKKalpha/beta phosphorylation. J. Nutr. Biochem. 21, 1120–1126 (2010).

    Article  CAS  Google Scholar 

  12. Ohsaki, Y. et al. Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci., Biotechnol., Biochem. 70, 926–932 (2006).

    Article  CAS  Google Scholar 

  13. Gong, T., Yang, Y., Jin, T., Jiang, W. & Zhou, R. Orchestration of NLRP3 inflammasome activation by ion fluxes. Trends Immunol. 39, 393–406 (2018).

    Article  CAS  Google Scholar 

  14. Gong, T., Jiang, W. & Zhou, R. Control of inflammasome activation by phosphorylation. Trends Biochem Sci. 43, 685–699 (2018).

    Article  CAS  Google Scholar 

  15. Tang, T., Gong, T., Jiang, W. & Zhou, R. GPCRs in NLRP3 inflammasome activation, regulation, and therapeutics. Trends Pharm. Sci. 39, 798–811 (2018).

    Article  CAS  Google Scholar 

  16. Mortimer, L., Moreau, F. & MacDonald, J. A. NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations. Nat. Immunol. 17, 1176–1186 (2016).

    Article  CAS  Google Scholar 

  17. Jiang, H. et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J. Exp. Med. 214, 3219–3238 (2017).

    Article  CAS  Google Scholar 

  18. Huang, Y. et al. Tranilast directly targets NLRP3 to treat inflammasome-driven diseases. EMBO Mol. Med. 10, e8689 (2018).

    Article  Google Scholar 

  19. He, H. et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat. Commun. 9, 2550 (2018).

    Article  Google Scholar 

  20. Yan, Y. et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38, 1154–1163 (2013).

    Article  CAS  Google Scholar 

  21. Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).

    Article  CAS  Google Scholar 

  22. Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011).

    Article  CAS  Google Scholar 

  23. Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).

    Article  CAS  Google Scholar 

  24. Xu, H. et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 513, 237–241 (2014).

    Article  CAS  Google Scholar 

  25. Gurung, P., Lukens, J. R. & Kanneganti, T. D. Mitochondria: diversity in the regulation of the NLRP3 inflammasome. Trends Mol. Med. 21, 193–201 (2015).

    Article  CAS  Google Scholar 

  26. He, Y., Zeng, M. Y., Yang, D., Motro, B. & Nunez, G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530, 354–357 (2016).

    Article  CAS  Google Scholar 

  27. Shi, H. et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat. Immunol. 17, 250–258 (2016).

    Article  CAS  Google Scholar 

  28. Swanson, K. V. & Deng, M. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489 (2019).

    Article  CAS  Google Scholar 

  29. So, A. K. & Martinon, F. Inflammation in gout: mechanisms and therapeutic targets. Nat. Rev. Rheumatol. 13, 639–647 (2017).

    Article  CAS  Google Scholar 

  30. Tanaka, S. et al. Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kappaB activation. Clin. Exp. Immunol. 160, 283–292 (2010).

    Article  CAS  Google Scholar 

  31. Harshman, S. G. & Shea, M. K. The role of vitamin K in chronic aging diseases: inflammation, cardiovascular disease, and osteoarthritis. Curr. Nutr. Rep. 5, 90–98 (2016).

    Article  CAS  Google Scholar 

  32. Hodges, S. J., Pilkington, M. J., Shearer, M. J., Bitensky, L. & Chayen, J. Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8. Clin. Sci. (Lond., Engl.: 1979). 78, 63–66 (1990).

    Article  CAS  Google Scholar 

  33. Shearer, M. J. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. 23, 49–59 (2009).

    Article  CAS  Google Scholar 

  34. Conly, J. & Stein, K. Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials. Clin. Invest. Med. Med. Clin. et. Exp. 17, 531–539 (1994).

    CAS  Google Scholar 

  35. Kuwabara, A. et al. High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease. Osteoporos. Int. 20, 935–942 (2009).

    Article  CAS  Google Scholar 

  36. Misra, D. et al. Vitamin K deficiency is associated with incident knee osteoarthritis. Am. J. Med. 126, 243–248 (2013).

    Article  CAS  Google Scholar 

  37. Wolf, P., Hupfeld, C., Dorrestein, G. & Kamphues, J. Investigations in pet birds (Agapornis spp.) fed different vitamin K contents in the diet. J. Anim. Physiol. Anim. Nutr. 89, 222–228 (2005).

    Article  CAS  Google Scholar 

  38. Ho, P. C. & Wong, V. K. Influence of DL methionine and sodium metabisulphite on the photostability of vitamin k1. PDA J. Pharm. Sci. Technol. 52, 129–133 (1998).

    CAS  PubMed  Google Scholar 

  39. Hassan G. S. Menadione. Profiles of Drug Substances, Excipients and Related Methodology. 227–313, Vol. 38 (Elsevier; 2013).

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Acknowledgements

This research was supported by the National Key Research and Development Program of China (grant number 2019YFA0508503), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant number XDB29030102), the National Natural Science Foundation of China (grant numbers 81701549, 91742202, 81525013, 81722022, and 81821001), the Young Talent Support Program and Fundamental Research Funds for the Central Universities and the University Synergy Innovation Program of Anhui Province (GXXT-2019-026).

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  1. These authors contributed equally: Xicui Zheng, Yingting Hou

Authors and Affiliations

  1. The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Xicui Zheng, Hongbin He & Xiaqiong Wang

  2. Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Xicui Zheng, Yingting Hou, Hongbin He, Yun Chen, Rongbin Zhou, Xiaqiong Wang, Tao Gong & Wei Jiang

  3. CAS Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei, 230027, China

    Rongbin Zhou

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  1. Xicui Zheng
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Contributions

C.Z., Y.H., B.H., Y.C., and X.W. performed the experiments. R.Z., X.W., T.G., and W.J. designed the research. T.G., W.J., and R.Z. wrote the manuscript. W.J. supervised the project.

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Correspondence to Xiaqiong Wang, Tao Gong or Wei Jiang.

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Zheng, X., Hou, Y., He, H. et al. Synthetic vitamin K analogs inhibit inflammation by targeting the NLRP3 inflammasome. Cell Mol Immunol 18, 2422–2430 (2021). https://doi.org/10.1038/s41423-020-00545-z

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