Kupffer Cell Engulfment of Apoptotic Bodies Stimulates Death Ligand and Cytokine Expression

Ali Canbay, Ariel E. Feldstein, Hajime Higuchi, Nate Werneburg, Annette Grambihler, Steve F. Bronk, Gregory J. Gores

Research output: Contribution to journalArticle

309 Scopus citations

Abstract

Hepatocyte apoptosis by death receptors, hepatic inflammation, and fibrosis are prominent features of liver diseases. However, the link between these processes remains unclear. Our aim was to ascertain whether engulfment of apoptotic bodies by Kupffer cells promotes hepatic inflammation and fibrosis. Isolated murine Kupffer cells efficiently engulfed apoptotic bodies generated from UV-treated mouse hepatocytes. Engulfment of the apoptotic bodies, but not latex beads, stimulated Kupffer cell generation of death ligands, including Fas ligand, and tumor necrosis factor α (TNF-α). Both apoptotic body phagocytosis and death ligand generation were attenuated by gadolinium chloride, a Kupffer cell toxicant. Kupffer cells isolated from 3-day bile duct-ligated (BDL) mice were phenotypically similar to apoptotic body-"fed" Kupffer cells with enhanced death ligand expression; inhibition of hepatocyte apoptosis with a caspase inhibitor prevented this Kupffer cell activation. Consistent with a role for Kupffer cells in liver inflammation and fibrosis, gadolinium chloride attenuated neutrophil infiltration and markers for stellate cell activation. In conclusion, these findings support a model of cholestatic liver injury where Kupffer cell engulfment of apoptotic bodies promotes inflammation and fibrogenesis.

Original languageEnglish (US)
Pages (from-to)1188-1198
Number of pages11
JournalHepatology
Volume38
Issue number5
DOIs
StatePublished - Nov 2003

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ASJC Scopus subject areas

  • Hepatology

Cite this

Canbay, A., Feldstein, A. E., Higuchi, H., Werneburg, N., Grambihler, A., Bronk, S. F., & Gores, G. J. (2003). Kupffer Cell Engulfment of Apoptotic Bodies Stimulates Death Ligand and Cytokine Expression. Hepatology, 38(5), 1188-1198. https://doi.org/10.1053/jhep.2003.50472