Bile acid analogues are activators of pyrin inflammasome
| Autor: | Xinming Cai, Zinger Yang, John S. Reece-Hoyes, Edmund Harrington, John Alford, Tim Schuhmann, Luis Llamas, Rob Maher, Alicia Lindeman, Stephen M. Canham, Irina Alimov, Nadire Cochran, Carsten Russ, Suchithra Menon, Gregory R. Hoffman, Qiong Wang, John Concannon |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Inflammasomes THP-1 Cells medicine.drug_class Gut flora digestive system Biochemistry Pyrin domain Bile Acids and Salts 03 medical and health sciences Immune system medicine Humans Myeloid Cells Editors' Picks Microbiome Intestinal Mucosa Immunity Mucosal Molecular Biology 030102 biochemistry & molecular biology biology Bile acid Chemistry Pyroptosis Epithelial Cells Inflammasome Cell Biology Pyrin biology.organism_classification MEFV Gastrointestinal Microbiome 030104 developmental biology medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 294:3359-3366 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra118.005103 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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