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Nonresolving Inflammation in gp91^phox–/– Mice, a Model of Human Chronic Granulomatous Disease, Has Lower Adenosine and Cyclic Adenosine 5'-Monophosphate¹

Ravindra Rajakariar^*, Justine Newson, Edwin K. Jackson, Precilla Sawmynaden, Andrew Smith, Farooq Rahman, Muhammad M. Yaqoob^* and Derek W. Gilroy^2,

^* Department of Experimental Medicine and Translational Therapeutics, William Harvey Research Institute, London, United Kingdom; Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, United Kingdom; Center for Clinical Pharmacology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, and Centre for Molecular Medicine, Division of Medicine, University College London, London, United Kingdom

In chronic granulomatous disease (CGD), there is failure to generate reactive oxygen metabolites, resulting in recurrent infections and persistent inflammatory events. Because responses to sterile stimuli in murine models of CGD also result in nonresolving inflammation, we investigated whether defects in endogenous counterregulatory mechanisms and/or proresolution pathways contribute to the etiology of CGD. To this end, we conducted a series of experiments finding, in the first instance that adenosine and cAMP, which dampen innate immune-mediated responses, show a biphasic profile in resolving peritonitis; peaking at onset, waning as inflammation progresses, and rising again at resolution. We also found elevations in adenosine and cAMP in resolving human peritonitis. In gp91^phox–/– mice, an experimental model of CGD, levels of adenosine and cAMP were significantly lower at onset and again at resolution. Corroborating the finding of others, we show that adenosine, signaling through its A_2A receptor and therefore elevating cAMP, is not only anti-inflammatory, but, importantly, it does not impair proresolution pathways, properties typical of nonsteroidal anti-inflammatory drugs. Conversely, antagonizing the A_2A receptor worsens acute inflammation and prolongs resolution. Taking this further, activating the A_2A receptor in gp91^phox–/– mice was dramatically anti-inflammatory regardless of the phase the inflammatory response A_2A agonists were administered, i.e., onset or resolution, demonstrating wide and robust pharmacological flexibility that is unlikely to subvert proresolution pathways. Therefore, we describe the biphasic profile of adenosine and cAMP throughout the time course of acute inflammation that is dysregulated in CGD.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ D.W.G. is a Wellcome Trust-funded Career Development Fellow, and R.R. is a Kidney Research United Kingdom-Funded Clinical Research Fellow. E.K.J is supported by National Institutes of Health Grant DK079307

² Address correspondence and reprint requests to Dr. Derek W. Gilroy, Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, U.K. E-mail address: d.gilroy{at}ucl.ac.uk

³ Abbreviations used in this paper: PMN, polymorphonuclear cell; CGD, chronic granulomatous disease; CSC, 8-(3-chlorostyryl)-caffeine; NSAID, nonsteroidal anti-inflammatory drug.