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

Xinshou Ouyang, Ayaz Ghani, Ahsan Malik, Tuere Wilder, Oscar Rene Colegio, Richard Anthony Flavell, Bruce Neil Cronstein and Wajahat Zafar Mehal ()
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Xinshou Ouyang: Section of Digestive Diseases, Yale University
Ayaz Ghani: Section of Digestive Diseases, Yale University
Ahsan Malik: Section of Digestive Diseases, Yale University
Tuere Wilder: New York University School of Medicine
Oscar Rene Colegio: Yale University
Richard Anthony Flavell: Yale University
Bruce Neil Cronstein: New York University School of Medicine
Wajahat Zafar Mehal: Section of Digestive Diseases, Yale University

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: 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 A2A 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 A2A receptor-mediated signalling.

Date: 2013
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DOI: 10.1038/ncomms3909

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