1. Academic Validation
  2. Bile acid analogues are activators of pyrin inflammasome

Bile acid analogues are activators of pyrin inflammasome

  • J Biol Chem. 2019 Mar 8;294(10):3359-3366. doi: 10.1074/jbc.RA118.005103.
Irina Alimov 1 Suchithra Menon 1 Nadire Cochran 1 Rob Maher 1 Qiong Wang 1 John Alford 1 John B Concannon 1 Zinger Yang 1 Edmund Harrington 1 Luis Llamas 1 Alicia Lindeman 1 Gregory Hoffman 1 Tim Schuhmann 2 Carsten Russ 1 John Reece-Hoyes 1 Stephen M Canham 3 Xinming Cai 4
Affiliations

Affiliations

  • 1 From the Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139 and.
  • 2 the Novartis Institute for Biomedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.
  • 3 From the Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139 and steve.canham@novartis.com.
  • 4 From the Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139 and xinming.cai@sanofi.com.
Abstract

Bile acids are critical metabolites in the gastrointestinal tract and contribute to maintaining intestinal immune homeostasis through cross-talk with the gut microbiota. The conversion of bile acids by the gut microbiome is now recognized as a factor affecting both host metabolism and immune responses, but its physiological roles remain unclear. We conducted a screen for microbiome metabolites that would function as inflammasome activators and herein report the identification of 12-oxo-lithocholic acid (BAA485), a potential microbiome-derived bile acid metabolite. We demonstrate that the more potent analogue 11-oxo-12S-hydroxylithocholic acid methyl ester (BAA473) can induce secretion of interleukin-18 (IL-18) through activation of the inflammasome in both myeloid and intestinal epithelial cells. Using a genome-wide CRISPR screen with compound induced Pyroptosis in THP-1 cells, we identified that inflammasome activation by BAA473 is pyrin-dependent (MEFV). To our knowledge, the bile acid analogues BAA485 and BAA473 are the first small molecule activators of the pyrin inflammasome. We surmise that pyrin inflammasome activation through microbiota-modified bile acid metabolites such as BAA473 and BAA485 plays a role in gut microbiota regulated intestinal immune response. The discovery of these two bioactive compounds may help to further unveil the importance of pyrin in gut homeostasis and autoimmune diseases.

Keywords

CRISPR screen; CRISPR/Cas; autoimmune disease; bile acid; biotransformation; familial Mediterranean fever; gut homeostasis; immune response; inflammasome; microbiome; microbiota; mucosal immunology; pyrin.

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