title: Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome.
abstract: 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-1β 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.
authors.affiliation: Department of Microbiology & Immunology, Columbia University, New York, New York 10032, USA.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Abdul-Sater
authors.forename: Ivan
authors.initials: I
authors.lastname: Tattoli
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Andrzej
authors.initials: A
authors.lastname: Grajkowski
authors.forename: Assaf
authors.initials: A
authors.lastname: Levi
authors.forename: Beverly H
authors.initials: BH
authors.lastname: Koller
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
authors.forename: Serge L
authors.initials: SL
authors.lastname: Beaucage
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.forename: Christian
authors.initials: C
authors.lastname: Schindler
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099197:STING Protein
chemical_list: D002118:Calcium; D002352:Carrier Proteins; D006152:Cyclic GMP; D015226:Dinucleoside Phosphates; D058847:Inflammasomes; D053583:Interleukin-1beta; D008565:Membrane Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium; D017382:Reactive Oxygen Species; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C532857:STING1 protein, human; D000099197:STING Protein; C528998:cyclic diadenosine phosphate; C062025:bis(3',5')-cyclic diguanylic acid