Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Calcium; Carrier Proteins; Cell Line, Tumor; Cyclic GMP; Dinucleoside Phosphates; Humans; Inflammasomes; Interleukin-1beta; Macrophages; Membrane Potential, Mitochondrial; Membrane Proteins; Mice; Mice, Inbred C57BL; Potassium; Reactive Oxygen Species
The cyclic dinucleotides 3'-5'diadenylate (c-diAMP) and 3'-5' diguanylate (c-diGMP) are important bacterial second messengers that have recently been shown to stimulate the secretion of type I Interferons (IFN-Is) through the c-diGMP-binding protein MPYS/STING. Here, we show that physiologically relevant levels of cyclic dinucleotides also stimulate a robust secretion of IL-1beta through the NLRP3 inflammasome. Intriguingly, this response is independent of MPYS/STING. Consistent with most NLRP3 inflammasome activators, the response to c-diGMP is dependent on the mobilization of potassium and calcium ions. However, in contrast to other NLRP3 inflammasome activators, this response is not associated with significant changes in mitochondrial potential or the generation of mitochondrial reactive oxygen species. Thus, cyclic dinucleotides activate the NLRP3 inflammasome through a unique pathway that could have evolved to detect pervasive bacterial pathogen-associated molecular patterns associated with intracellular infections.
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Citation: EMBO Rep. 2013 Oct;14(10):900-6. doi: 10.1038/embor.2013.132. Epub 2013 Sep 6. Link to article on publisher's site
Abdul-Sater, Ali A.; Tattoli, Ivan; Jin, Lei; Grajkowski, Andrzej; Levi, Assaf; Koller, Beverly H.; Allen, Irving C.; Beaucage, Serge L.; Fitzgerald, Katherine A.; Ting, Jenny P-Y.; Cambier, John C.; Girardin, Stephen E.; and Schindler, Christian, "Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome" (2013). University of Massachusetts Medical School Faculty Publications. 739.