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 Tr^−/−Mdr2^−/− 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 Tr^−/−Mdr2^−/− mice had elevated liver weights and serum alanine transferase values. However, fibrosis was primarily periductular in Mdr2^−/− mice, compared with extensive bridging fibrosis in Tr^−/−Mdr2^−/− mice. DR cell population was greatly expanded in the Tr^−/−Mdr2^−/− versus 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 time-of-flight mass cytometry, total macrophages were more abundant in Tr^−/−Mdr2^−/− 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.