Systemic illness triggered by microbial invasion of normally sterile parts of the body is referred to as sepsis. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. Current concepts suggest that organ failure and mortality in sepsis are caused by inappropriate regulation of the immune system, which manifests as excessive inflammation in the presence of immunosuppression. Recent evidence gathered in our laboratory suggests that extracellular adenosine that accumulates during sepsis modulates the immune system by activating adenosine receptors on the surface of immune cells. The production of extracellular adenosine is the consequence of the cellular release of its precursors ATP and ADP, and their sequential cell surface phosphohydrolysis to AMP by ectonucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1, CD39) and then to adenosine by ecto-5'-nucleotidase (Ecto5'Ntase, CD73). We found that both CD39 and CD73 are upregulated during sepsis and have pivotal roles in restraining inflammation and organ damage by initiating adenosine receptor signaling.
Specific Aim 1 will test the precise mechanisms by which CD39 and CD73 prevent excessive inflammation and organ injury during sepsis using adoptive cell transfer techniques, the cre-lox techology, and ex vivo studies on innate immune cells.
Specific Aim 2 will define the molecular basis of the upregulation of CD39 and CD73 on macrophages, which may serve to curb excessive macrophage activation by producing adenosine during sepsis. The overarching goal here is to delineate the role of the ectonucleotidase cascade consisting of CD39 and CD73 in protecting against sepsis and to determine whether this cascade can be therapeutically targeted to manage patients with sepsis.

Public Health Relevance

Sepsis remains the leading cause of morbidity and mortality in critically ill patients. We are studying the function of two ectonucleotidases, CD39 and CD73, which have recently been shown to have beneficial immunomodulatory effects in sepsis. By elucidating how CD39 and CD73 modulate immune and organ function during sepsis, we can utilize this information to develop new pharmacologic approaches targeting CD39 and CD73 to treat patients suffering from sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066189-11
Application #
8900797
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2002-07-01
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
11
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Rutgers University
Department
Surgery
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
Haskó, György; Antonioli, Luca; Cronstein, Bruce N (2018) Adenosine metabolism, immunity and joint health. Biochem Pharmacol 151:307-313
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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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