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

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...

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Bibliographic Details
Published inNature communications Vol. 4; p. 2909
Main Authors Ouyang, Xinshou, Ghani, Ayaz, Malik, Ahsan, Wilder, Tuere, Colegio, Oscar Rene, Flavell, Richard Anthony, Cronstein, Bruce Neil, Mehal, Wajahat Zafar
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group 01.12.2013
Subjects
Adenosine
Chronic illnesses
Cytokines
Kinases
Ligands
Metabolites
Pathogens
Proteins
New York
United States > US
Connecticut
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Summary: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.
ISSN:2041-1723
DOI:10.1038/ncomms3909