A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation

Balázs Csóka, Zoltán H. Németh, Peter Rosenberger, Holger K. Eltzschig, Zoltán Spolarics, Pál Pacher, Zsolt Selmeczy, Balázs Koscsó, Leonóra Himer, E. Sylvester Vizi, Michael R. Blackburn, Edwin A. Deitch, György Haskó

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Abstract

Despite intensive research, efforts to reduce the mortality of septic patients have failed. Adenosine is a potent extracellular signaling molecule, and its levels are elevated in sepsis. Adenosine signals through G-protein-coupled receptors and can regulate the host's response to sepsis. In this study, we studied the role of A2B adenosine receptors in regulating the mortality and inflammatory response of mice following polymicrobial sepsis. Genetic deficiency of A2B receptors increased the mortality of mice suffering from cecal ligation and puncture-induced sepsis. The increased mortality of A2B knockout mice was associated with increased levels of inflammatory cytokines and chemokines and augmented NF-κB and p38 activation in the spleen, heart, and plasma in comparison with wild-type animals. In addition, A2B receptor knockout mice showed increased splenic apoptosis and phosphatase and tensin homolog activation and decreased Akt activation. Experiments using bone-marrow chimeras revealed that it is the lack of A2B receptors on nonhematopoietic cells that is primarily responsible for the increased inflammation of septic A2B receptor-deficient mice. These results indicate that A2B receptor activation may offer a new therapeutic approach for the management of sepsis.

Original languageEnglish
Pages (from-to)542-550
Number of pages9
JournalJournal of Immunology
Volume185
Issue number1
DOIs
Publication statusPublished - Jul 1 2010

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Csóka, B., Németh, Z. H., Rosenberger, P., Eltzschig, H. K., Spolarics, Z., Pacher, P., Selmeczy, Z., Koscsó, B., Himer, L., Vizi, E. S., Blackburn, M. R., Deitch, E. A., & Haskó, G. (2010). A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation. Journal of Immunology, 185(1), 542-550. https://doi.org/10.4049/jimmunol.0901295