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Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage

Abstract

Inappropriate or prolonged inflammation is the main cause of many diseases1; for this reason it is important to understand the physiological mechanisms that terminate inflammation in vivo2. Agonists for several Gs-protein-coupled receptors3, including cell-surface adenosine purinergic receptors4,5,6,7, can increase levels of immunosuppressive cyclic AMP in immune cells8,9,10,11,12,13,14,15; however, it was unknown whether any of these receptors regulates inflammation in vivo. Here we show that A2a adenosine receptors have a non-redundant role in the attenuation of inflammation and tissue damage in vivo. Sub-threshold doses of an inflammatory stimulus16,17 that caused minimal tissue damage in wild-type mice were sufficient to induce extensive tissue damage, more prolonged and higher levels of pro-inflammatory cytokines, and death of male animals deficient in the A2a adenosine receptor. Similar observations were made in studies of three different models of inflammation and liver damage as well as during bacterial endotoxin-induced septic shock. We suggest that A2a adenosine receptors are a critical part of the physiological negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses.

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Figure 1: Pharmacological activation of Adora2a or other Gs-protein-coupled receptors in vivo prevents Con A-induced liver damage and pro-inflammatory TNF-α accumulation in vivo.
Figure 2: Enhanced and prolonged accumulation of pro-inflammatory cytokines and exaggerated liver damage in A2a-receptor-deficient mice.
Figure 3: Pharmacological inactivation of A2a receptors in vivo by antagonist ZM241385 exacerbates Con A- (a) and PEA-induced (b) liver damage.
Figure 4: Enhanced accumulation of pro-inflammatory cytokines and tissue damage in A2a-receptor-deficient mice treated with endotoxin.

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Acknowledgements

We thank J. Fan Chen, S. Fink and M. A. Schwartzschild for providing A2a receptor gene deficient mice; W. E. Paul, R. N. Germain, S. Apasov, P. Smith and P. M. Murphy for support, discussions and help; and J. Kinsel and S. Starnes for help in preparation of the manuscript.

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Correspondence to Michail Sitkovsky.

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Ohta, A., Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414, 916–920 (2001). https://doi.org/10.1038/414916a

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