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Tumor necrosis factor-related apoptosis-inducing ligand receptor deficiency promotes the ductular reaction, macrophage accumulation, and hepatic fibrosis in the Mdr2 -/- mouse

Krishnan, A., Katsumi, T., Guicciardi, M.E. et al.

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 TRAIL receptor signaling in a mouse model of cholestatic liver injury. TRAIL receptor-deficient (Tr-/-) mice were crossbred with ATP binding cassette subfamily B member 4-deficient (Abcb4-/-or 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.

Citation

Krishnan, A., Katsumi, T., Guicciardi, M.E. et al. "Tumor necrosis factor-related apoptosis-inducing ligand receptor deficiency promotes the ductular reaction, macrophage accumulation, and hepatic fibrosis in the Mdr2 -/- mouse" American Journal of Pathology (2020): 30135-8