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Nat Commun. 2013;4:2909. doi: 10.1038/ncomms3909.

Adenosine is required for sustained inflammasome activation via the A₂A receptor and the HIF-1α pathway.

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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.
Section of Digestive Diseases, Yale University, TAC S223A, New Haven, Connecticut 06520, USA.
Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
Department of Immunobiology, Yale University, TAC S569A, New Haven, Connecticut 06520, USA.


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.

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