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

ABSTRACT: 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.

SUBMITTER: Krishnan A 

PROVIDER: S-EPMC7280758 | biostudies-literature |

REPOSITORIES: biostudies-literature