TRAIL Receptor Deficiency Promotes the Ductular Reaction, Macrophage Accumulation and Hepatic Fibrosis in the Mdr2-/- Mouse.

The tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptor (TR) is a pro-apoptotic receptor whose contribution to chronic cholestatic liver disease is unclear. Herein, we examined TR signaling in a mouse model of cholestatic liver injury. TRAIL receptor deficient (Tr(-/-)) mice were crossbred with ATP binding cassette SubfamilyB member 4 deficient (Abcb4(-/-)or Mdr2(-/-)) mice. Male and female wild type (WT), Tr(-/-), Mdr2(-/ -) and Tr(-/-)Mdr2(-/-) mice were assessed for liver injury, fibrosis and ductular reactive (DR) cells. Macrophage subsets were examined by high dimensional mass cytometry (CyTOF). Mdr2(-/-) and Tr(-/-)Mdr2(-/-) mice had elevated liver weights and serum ALT values. However, fibrosis was primarily periductular in Mdr2(-/-) mice, as compared to extensive bridging fibrosis in Tr(-/-)Mdr2(-/-) mice. DR cell population was greatly expanded in the Tr(-/-)Mdr2(-/-) vs Mdr2(-/-) mice. The expanded DR cell population in Tr(-/-)Mdr2(-/-) mice was due to decreased cell loss by apoptosis and not enhanced proliferation. As assessed by CyTOF, total macrophages were more abundant in Tr(-/-)Mdr2(-/-) vs Mdr2(-/-) mice suggesting the DR cell population promotes macrophage associated hepatic inflammation. Inhibition of monocyte derived recruited macrophages using the CCR2/CCR5 antagonist cenicriviroc in the Mdr2(-/-) mice resulted in further expansion of the DR cell population. In conclusion, genetic deletion of TRAIL receptor increased the DR cell population, macrophage accumulation and hepatic fibrosis in the Mdr2(-/-) model of cholestasis.