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Adenosine A_2A Receptor Inactivation Increases Survival in Polymicrobial Sepsis¹

Zoltán H. Németh^*, Balázs Csóka^*, Jeanette Wilmanski^*, DaZhong Xu^*, Qi Lu^*, Catherine Ledent, Edwin A. Deitch^*, Pál Pacher, Zoltán Spolarics^* and György Haskó^2,*

^* Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103; Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, Université Libre de Bruxelles, Brussels, Belgium; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892

The mechanisms governing the impairment of bacterial clearance and immune function in sepsis are not known. Adenosine levels are elevated during tissue hypoxia and damage associated with sepsis. Adenosine has strong immunosuppressive effects, many of which are mediated by A_2A receptors (A_2AR) expressed on immune cells. We examined whether A_2AR are involved in the regulation of immune function in cecal ligation and puncture-induced murine polymicrobial sepsis by genetically or pharmacologically inactivating A_2AR. A_2AR knockout (KO) mice were protected from the lethal effect of sepsis and had improved bacterial clearance compared with wild-type animals. cDNA microarray analysis and flow cytometry revealed increased MHC II expression in A_2A-inactivated mice, suggesting improved Ag presentation as a mechanism of protection. Apoptosis was attenuated in the spleen of A_2A KO mice indicating preserved lymphocyte function. Levels of the immunosuppressive cytokines IL-10 and IL-6 were markedly lower following A_2AR blockade. Similar to observations with A_2AR KO mice, an A_2AR antagonist increased survival even when administered in a delayed fashion. These studies demonstrate that A_2AR blockade may be useful in the treatment of infection and sepsis.

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