The pathogenesis of
primary sclerosing cholangitis (PSC) and the mechanistic link to
inflammatory bowel disease remain ill-defined. Ectonucleoside
triphosphate diphosphohydrolase-1 (ENTPD1)/clusters of differentiation (CD) 39, the dominant purinergic ecto-
enzyme, modulates intestinal
inflammation. Here, we have explored the role of CD39 in biliary injury and
fibrosis. The impact of CD39 deletion on disease severity was studied in
multidrug resistance protein 2 (Mdr2)-/- and
3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse models of
sclerosing cholangitis and biliary
fibrosis. Antibody-mediated CD8+ T-cell depletion, selective gut decontamination, experimental
colitis, and administration of stable
adenosine triphosphate (
ATP) agonist were performed.
Retinoic acid-induced gut imprinting on T cells was studied in vitro. Over half of Mdr2-/-;CD39-/- double mutants, expected by Mendelian genetics, died in utero. Compared to Mdr2-/-;CD39+/+, surviving Mdr2-/-;CD39-/- mice demonstrated exacerbated liver injury,
fibrosis, and ductular reaction. CD39 deficiency led to a selective increase in hepatic CD8+ T cells and
integrin α4β7, a T-cell gut-tropism receptor. CD8+ cell depletion in Mdr2-/-;CD39-/- mice diminished hepatobiliary injury and
fibrosis. Treatment with
antibiotics attenuated, whereas
dextran sulfate sodium-induced
colitis exacerbated,
liver fibrosis in Mdr2-/- mice. Colonic administration of αβ-
ATP into CD39-sufficient Mdr2-/- mice triggered hepatic CD8+ cell influx and recapitulated the severe phenotype observed in Mdr2-/-;CD39-/- mice. In vitro, addition of
ATP promoted the
retinoic acid-induced imprinting of gut-homing
integrin α4β7 on naive CD8+ cells. CD39 expression was relatively low in human normal or PSC livers but abundantly present on immune cells of the colon and further up-regulated in samples of patients with
inflammatory bowel disease. Conclusion: CD39 deletion promotes biliary injury and
fibrosis through gut-imprinted CD8+ T cells. Pharmacological modulation of purinergic signaling may represent a promising approach for the treatment of PSC. (Hepatology Communications 2017;1:957-972).