Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor Deficiency Promotes the Ductular Reaction, Macrophage Accumulation, and Hepatic Fibrosis in the Abcb4 Mouse.

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; TNFSF10) receptor (TR) is a pro-apoptotic receptor whose contribution to chronic cholestatic liver disease is unclear. Herein, we examined TRAIL receptor signaling in a mouse model of cholestatic liver injury. TRAIL receptor-deficient (Tnsf10 or Tr) mice were crossbred with ATP binding cassette subfamily B member 4-deficient (Abcb4, alias Mdr2) mice. Male and female wild-type, Tr, Mdr2, and TrMdr2 mice were assessed for liver injury, fibrosis, and ductular reactive (DR) cells. Macrophage subsets were examined by high-dimensional mass cytometry (time-of-flight mass cytometry). Mdr2 and TrMdr2 mice had elevated liver weights and serum alanine transferase values. However, fibrosis was primarily periductular in Mdr2 mice, compared with extensive bridging fibrosis in TrMdr2 mice. DR cell population was greatly expanded in the TrMdr2 versus Mdr2 mice. The expanded DR cell population in TrMdr2 mice was due to decreased cell loss by apoptosis and not enhanced proliferation. As assessed by time-of-flight mass cytometry, total macrophages were more abundant in TrMdr2 versus 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.