Ecto-5′-Nucleotidase (CD73) Decreases Mortality and Organ Injury in Sepsis

Abstract

The extracellular concentrations of adenosine are elevated during sepsis and adenosine receptors regulate the host’s response to sepsis. Here, we investigated the role of the adenosine generating ectoenzyme, ecto-5′-nucleotidase (CD73) in regulating immune and organ function during sepsis. Polymicrobial sepsis was induced by subjecting CD73 knockout (KO) and wild type (WT) mice to cecal ligation and puncture. CD73 KO mice showed increased mortality in comparison with WT mice, which was associated with increased bacterial counts and elevated inflammatory cytokine and chemokine concentrations in the blood and peritoneum. CD73 deficiency promoted lung injury as indicated by increased myeloperoxidase activity and neutrophil infiltration, and elevated pulmonary cytokine levels. CD73 KO mice had increased apoptosis in the thymus, as evidenced by increased activation of caspase-3, poly(ADP-ribose) polymerase and NF-κB. Septic CD73 KO mice had higher blood urea nitrogen levels and elevated cytokine levels in the kidney, indicating increased renal dysfunction. The increased kidney injury of CD73 KO mice was associated with augmented activation of p38 MAPK and decreased phosphorylation of Akt. Pharmacological inactivation of CD73 in WT mice using AMPCP augmented cytokine levels in the blood and peritoneal lavage fluid. These findings suggest that CD73-derived adenosine may be beneficial in sepsis.

The Guanosine-Adenosine Interaction Exists In Vivo

“…There is now an overwhelming body of evidence in support of the conclusion that adenosine (Okusa et al, 1999(Okusa et al, , 2000(Okusa et al, , 2001Emala, 2000, 2002;Okusa, 2002;Day et al, 2003Day et al, , 2005Lee et al, 2004aLee et al, ,b, 2007Grenz et al, 2007aGrenz et al, ,b, 2008Grenz et al, , 2011Grenz et al, , 2012Kim et al, 2009;Haskó et al, 2011) and inosine (Maggio et al, 1980;Marberger et al, 1980;Fitzpatrick et al, 1981;Rothwell et al, 1981;Mathur and Ramsey, 1983) protect the kidneys from acute injury. Less well known is the fact that guanosine is also renoprotective (Kelly et al, 2001).…”

Extracellular Nucleotide Catabolism by the Group B Streptococcus Ectonucleotidase NudP Increases Bacterial Survival in Blood

“…In contrast, few studies have address the function of eATP/eAdo receptors during infections by extracellular pathogens and hence the biological consequences of modulating the eATP/eADP ratio (14,51). In mammals, the two main ectonucleotidases, CD39 and CD73, expressed at the surface of immune cells control the eATP/ eAdo ratio, and their inactivation is detrimental to the clearance of polymicrobial infections (13,52). This eATP/eAdo ratio serves as a central hub to control the balance between pro-and anti-inflammatory responses.…”

Role of CD73 and extracellular adenosine in disease

“…Hence, using fibroblasts with typically limited CD39 expression to study impact of NT5E deletion on calcification as done by St. Hilaire et al, although understandable, may not be the appropriate system to study vascular injury. Secondly, it is feasible that pyrophosphate might only be a substantive product of extracellular nucleotides in those vascular tissues where CD39 bioactivity is altered as in atherosclerosis [23], sepsis [24], transplant chronic rejection [25] or in the setting of genetic polymorphisms with altered ecto-enzymatic activity [14]. Such a scenario with altered CD39 bioactivity might explain the unusual distribution of arterial calcification seen in NT5E deficiency seen in this highly interesting publication.…”