Adenosine A2A receptor inactivation increases survival in polymicrobial sepsis

Zoltán H. Németh, Balázs Csóka, Jeanette Wilmanski, Da Zhong Xu, Qi Lu, Catherine Ledent, Edwin A. Deitch, Pál Pacher, Zoltán Spolarics, György Haskó

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91 Citations (Scopus)

Abstract

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 A2A receptors (A2AR) expressed on immune cells. We examined whether A2AR are involved in the regulation of immune function in cecal ligation and puncture-induced murine polymicrobial sepsis by genetically or pharmacologically inactivating A2AR. A2AR 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 A2A-inactivated mice, suggesting improved Ag presentation as a mechanism of protection. Apoptosis was attenuated in the spleen of A2A KO mice indicating preserved lymphocyte function. Levels of the immunosuppressive cytokines IL-10 and IL-6 were markedly lower following A2AR blockade. Similar to observations with A2AR KO mice, an A2AR antagonist increased survival even when administered in a delayed fashion. These studies demonstrate that A2AR blockade may be useful in the treatment of infection and sepsis.

Original languageEnglish
Pages (from-to)5616-5626
Number of pages11
JournalJournal of Immunology
Volume176
Issue number9
DOIs
Publication statusPublished - May 1 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Németh, Z. H., Csóka, B., Wilmanski, J., Xu, D. Z., Lu, Q., Ledent, C., Deitch, E. A., Pacher, P., Spolarics, Z., & Haskó, G. (2006). Adenosine A2A receptor inactivation increases survival in polymicrobial sepsis. Journal of Immunology, 176(9), 5616-5626. https://doi.org/10.4049/jimmunol.176.9.5616