11 June 2018
CD39 and CD73 are surface enzymes that jut into the extracellular space where they mediate the step-wise phosphohydrolysis of the autocrine and paracrine danger signals ATP and ADP into anti-inflammatory adenosine. Given the role of vascular and immune cells’ “purinergic halo” in maintaining homeostasis, we hypothesized that the ectonucleotidases CD39 and CD73 might play a protective role in lupus.
Lupus was modeled by intraperitoneal administration of pristane to three groups of mice: wild-type (WT), CD39 −/−, and CD73 −/−. After 36 weeks, autoantibodies, endothelial function, kidney disease, splenocyte activation/polarization, and neutrophil activation were characterized.
As compared with WT mice, CD39 −/− mice developed exaggerated splenomegaly in response to pristane, while both groups of ectonucleotidase-deficient mice demonstrated heightened anti-ribonucleoprotein production. The administration of pristane to WT mice triggered only subtle dysfunction of the arterial endothelium; however, both CD39 −/− and CD73 −/− mice demonstrated striking endothelial dysfunction following induction of lupus, which could be reversed by superoxide dismutase. Activated B cells and plasma cells were expanded in CD73 −/− mice, while deficiency of either ectonucleotidase led to expansion of T H17 cells. CD39 −/− and CD73 −/− mice demonstrated exaggerated neutrophil extracellular trap release, while CD73 −/− mice additionally had higher levels of plasma cell-free DNA.