The purine nucleoside adenosine is a biologically active extracellular signaling molecule that is formed at sites of metabolic stress associated with trauma and sepsis. Adenosine can bind to one or more of four cell surface receptors (A1, A2A, A2B, and A3) through which it exerts varying immunomodulatory effects. We have discovered that stimulation of A2A receptors with endogenous adenosine contributes to the mortality of mice subjected to a septic insult. This decreased survival of mice caused by A2A receptor stimulation was tightly associated with a capacity of A2A receptor activation to increase bacterial burden, to augment immune cell apoptosis, and to increase production of inflammatory cytokines. Further work performed suggests that adenosine has a more complex role in the pathophysiology of sepsis. Specifically, depending on which receptors are activated, adenosine differentially modulates immune function. For example, activation of A2B receptors by endogenous adenosine decreases the production of inflammatory cytokines in mice suffering from sepsis. Thus to better understand the complex regulatory pathways of the adenosine receptor system in sepsis, we propose the following highly integrated Specific Aims:
Aim 1 : Elucidate the role and relative importance of A1, A2A, A2B and A3 adenosine receptors in regulating immunity during sepsis.
Aim 2 : Elucidate the receptors and intracellular signaling pathways that mediate the modulatory effects of adenosine on the transcription and secretion of cytokines by macrophages stimulated with Gram-negative and Gram-positive bacteria. New knowledge about the control of septic immunity by distinct adenosine receptors could lead to the identification of novel pharmacological approaches for ameliorating the course of disease and preventing death in sepsis.
By elucidating how adenosine receptors modulate immune and organ function during sepsis, we can utilize this information to develop new pharmacologic approaches targeting adenosine receptors to treat patients suffering from sepsis.
|Haskó, György; Antonioli, Luca; Cronstein, Bruce N (2018) Adenosine metabolism, immunity and joint health. Biochem Pharmacol 151:307-313|
|Csóka, Balázs; Németh, Zoltán H; Szabó, Ildikó et al. (2018) Macrophage P2X4 receptors augment bacterial killing and protect against sepsis. JCI Insight 3:|
|Antonioli, Luca; Blandizzi, Corrado; Pacher, Pál et al. (2018) Quorum sensing in the immune system. Nat Rev Immunol 18:537-538|
|Csóka, Balázs; Németh, Zoltán H; Duerr, Claudia U et al. (2018) Adenosine receptors differentially regulate type 2 cytokine production by IL-33-activated bone marrow cells, ILC2s, and macrophages. FASEB J 32:829-837|
|Csóka, Balázs; Tör?, Gábor; Vindeirinho, Joana et al. (2017) A2A adenosine receptors control pancreatic dysfunction in high-fat-diet-induced obesity. FASEB J 31:4985-4997|
|Antonioli, Luca; Yegutkin, Gennady G; Pacher, Pál et al. (2016) Anti-CD73 in cancer immunotherapy: awakening new opportunities. Trends Cancer 2:95-109|
|Csóka, Balázs; Németh, Zoltán H; Tör?, Gábor et al. (2015) Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing. FASEB J 29:3626-37|
|Antonioli, Luca; Blandizzi, Corrado; Csóka, Balázs et al. (2015) Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations. Nat Rev Endocrinol 11:228-41|
|Csóka, Balázs; Németh, Zoltán H; Tör?, Gábor et al. (2015) CD39 improves survival in microbial sepsis by attenuating systemic inflammation. FASEB J 29:25-36|
|Antonioli, Luca; Haskó, György; Fornai, Matteo et al. (2014) Adenosine pathway and cancer: where do we go from here? Expert Opin Ther Targets 18:973-7|
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