A rapid administration of GW4064 inhibits the NLRP3 inflammasome activation independent of farnesoid X receptor agonism

  • FEBS Lett. 2017 Sep;591(18):2836-2847. doi: 10.1002/1873-3468.12782.
Shujun Xie  1 ,  Chuansheng Guo  2 ,  Zhexu Chi  2 ,  Bo Huang  1 ,  Yihua Wu  1 ,  Di Wang  2 ,  Dajing Xia  1
Affiliations
  • 1. Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, China.
  • 2. Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
PMID: 28787755 DOI: 10.1002/1873-3468.12782
Abstract

GW4064 is a small molecule known to be an agonist of the nuclear farnesoid X receptor (FXR). We found that GW4064 inhibits the NLR family CARD domain containing 3 (NLRP3) inflammasome activation in an FXR-independent manner as evidenced by its similar inhibitory effect on NLRP3 inflammasome activation in FXR-deficient macrophages. Interestingly, GW4064 decreases the nigericin-induced oligomerization and ubiquitination of ASC which is critical for the NLRP3 inflammasome activation. In vivo results indicate that GW4064 could partially rescue the symptoms of NLRP3-dependent inflammatory disease models. These results not only necessitate cautious interpretation of the biological function of GW4064 as an FXR Agonist, but also provide a potential therapeutic approach using GW4064 in the treatment of NLRP3-related diseases.

Keywords
FXR; GW4064; NLRP3 inflammasome.
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