Elevated ecto-5'-nucleotidase: a missing pathogenic factor and new therapeutic target for sickle cell disease

Area of Science:

• Biochemistry
• Hematology
• Pharmacology

Background:

• Excessive plasma adenosine is harmful in sickle cell disease (SCD), but the underlying molecular mechanisms are not fully understood.
• Soluble CD73, an enzyme that produces extracellular adenosine, has been implicated in adenosine-related pathologies.

Purpose of the Study:

• To elucidate the molecular mechanism of elevated circulating adenosine in SCD.
• To investigate the role of CD73 in SCD pathophysiology.
• To evaluate CD73 inhibition as a potential therapeutic strategy for SCD.

Main Methods:

• Assessed soluble CD73 activity in a murine model of SCD and correlated it with plasma adenosine levels.
• Utilized mouse genetic studies to determine CD73's contribution to SCD.
• Investigated erythrocyte adenosine 5'-monophosphate-activated protein kinase (AMPK) activation in SCD patients and mice.
• Administered a CD73 specific inhibitor (α,β-methylene adenosine 5'-diphosphate) to the SCD mouse model.

Main Results:

• Soluble CD73 activity and plasma adenosine were significantly elevated in the SCD mouse model.
• Genetic studies confirmed CD73's role in promoting sickling, hemolysis, and multiorgan damage in SCD.
• Erythrocyte AMPK was activated in both human SCD patients and the mouse model, downstream of ADORA2B signaling.
• CD73 inhibition markedly reduced sickling, hemolysis, multiorgan damage, and disease progression in mice.

Conclusions:

• CD73 activity is a key driver of excessive adenosine production and subsequent pathophysiology in SCD.
• AMPK activation, mediated by ADORA2B signaling, contributes to sickling via 2,3-BPG regulation.
• Targeting CD73 with specific inhibitors presents a promising therapeutic avenue for treating sickle cell disease.