Neutrophil A2A receptors in sepsis

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SUMMARY Sepsis is a clinical syndrome that complicates severe infection. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. There are no specific FDA-approved medicines for the treatment of sepsis. Current concepts of the pathophysiology of sepsis suggest that inappropriate regulation of neutrophil functions contribute to organ failure and mortality in sepsis. This manifests as an inability to control bacterial growth and dissemination, persistent and secondary infections, inflammation, and end organ injury. Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent immunosuppressive effects by binding to and activating G protein-coupled A2A adenosine receptors (ARs) on the surface of neutrophils. A2AAR signaling reproduces many of the phenotypic changes in neutrophils that are characteristic of sepsis, including decreased chemotaxis, diminished ability to ingest and kill bacteria and delayed apoptosis. Given this similarity between septic neutrophil alterations and the ones caused by A2AAR signaling, we hypothesized that endogenous adenosine would contribute to the sepsis-induced onset of neutrophil dysfunction via stimulation of A2AARs. Our preliminary data using both targeted genetic deletion and pharmacological antagonism in mice with cecal ligation and puncture-induced sepsis have confirmed that A2AARs contribute to bacterial dissemination, organ injury, and mortality. Our data with human patients demonstrate increased plasma adenosine and neutrophil A2AAR expression indicating increased A2AAR signaling leading to neutrophil dysfunction. Based on these data, we hypothesize that endogenous adenosine contributes to sepsis-induced immune dysregulation, bacterial dissemination, organ injury and mortality through A2AAR signaling in neutrophils. To address this hypothesis, we propose 2 Specific Aims. Specific Aim 1 will delineate the role of A2AAR signaling in neutrophils in contributing to bacterial dissemination, organ injury, and mortality in CLP-induced sepsis in mice. Specific Aim 2 will study the contribution of A2AAR signaling to neutrophil dysfunction in patients with sepsis. The long-term goal of this study is to pharmacologically target A2AAR signaling as a treatment option for the management of patients with sepsis.