title: Adenosine is required for sustained inflammasome activation via the A₂A receptor and the HIF-1α pathway.
abstract: Inflammasome pathways are important in chronic diseases; however, it is not known how the signalling is sustained after initiation. Inflammasome activation is dependent on stimuli such as lipopolysaccharide (LPS) and ATP that provide two distinct signals resulting in rapid production of interleukin (IL)-1β, with the lack of response to repeat stimulation. Here we report that adenosine is a key regulator of inflammasome activity, increasing the duration of the inflammatory response via the A(2A) receptor. Adenosine does not replace signals provided by stimuli such as LPS or ATP but sustains inflammasome activity via a cAMP/PKA/CREB/HIF-1α pathway. In the setting of the lack of IL-1β responses after previous exposure to LPS, adenosine can supersede this tolerogenic state and drive IL-1β production. These data reveal that inflammasome activity is sustained, after initial activation, by A(2A) receptor-mediated signalling.
authors.affiliation: 1] Section of Digestive Diseases, Yale University, TAC S223A, New Haven, Connecticut 06520, USA [2] Section of Digestive Diseases, Department of Veterans Affairs Connecticut Healthcare, West Haven, Connecticut 06516, USA.
authors.forename: Xinshou
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Section of Digestive Diseases, Yale University, TAC S223A, New Haven, Connecticut 06520, USA.
authors.forename: Ayaz
authors.initials: A
authors.lastname: Ghani
authors.affiliation: Section of Digestive Diseases, Yale University, TAC S223A, New Haven, Connecticut 06520, USA.
authors.forename: Ahsan
authors.initials: A
authors.lastname: Malik
authors.affiliation: Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Tuere
authors.initials: T
authors.lastname: Wilder
authors.affiliation: Department of Immunobiology, Yale University, TAC S569A, New Haven, Connecticut 06520, USA.
authors.forename: Oscar Rene
authors.initials: OR
authors.lastname: Colegio
authors.affiliation: Department of Immunobiology, Yale University, TAC S569A, New Haven, Connecticut 06520, USA.
authors.forename: Richard Anthony
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Bruce Neil
authors.initials: BN
authors.lastname: Cronstein
authors.affiliation: 1] Section of Digestive Diseases, Yale University, TAC S223A, New Haven, Connecticut 06520, USA [2] Section of Digestive Diseases, Department of Veterans Affairs Connecticut Healthcare, West Haven, Connecticut 06516, USA.
authors.forename: Wajahat Zafar
authors.initials: WZ
authors.lastname: Mehal
mesh_terms: D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D002352:Carrier Proteins; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D043705:Receptor, Adenosine A2A; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine