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

Anuradha Krishnan, Tomohiro Katsumi, Maria E. Guicciardi, Adiba I. Azad, Nazli B. Ozturk, Christy E. Trussoni, Gregory J. Gores

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1284-1297
Number of pages14
JournalAmerican Journal of Pathology
Volume190
Issue number6
DOIs
StatePublished - Jun 2020

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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