Article first published online: 8 AUG 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 3, pages 959–968, 2 September 2011
How to Cite
Connolly, M. K., Ayo, D., Malhotra, A., Hackman, M., Bedrosian, A. S., Ibrahim, J., Cieza-Rubio, N. E., Nguyen, A. H., Henning, J. R., Dorvil-Castro, M., Pachter, H. L. and Miller, G. (2011), Dendritic cell depletion exacerbates acetaminophen hepatotoxicity. Hepatology, 54: 959–968. doi: 10.1002/hep.24429
Potential conflict of interest: Nothing to report.
Supported in part by grants from a Liver Scholar Award from the American Liver Foundation (to G.M.), a Society of University Surgeons Junior Faculty Grant (to G.M.), and National Institute of Health Award DK085278 (to G.M.) and CA155649 (to G.M.).
- Issue published online: 25 AUG 2011
- Article first published online: 8 AUG 2011
- Accepted manuscript online: 13 MAY 2011 10:03AM EST
- Manuscript Accepted: 6 MAY 2011
- Manuscript Received: 17 NOV 2010
Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure in the United States and is primarily mediated by toxic metabolites that accumulate in the liver upon depletion of glutathione stores. However, cells of the innate immune system, including natural killer (NK) cells, neutrophils, and Kupffer cells, have also been implicated in the centrilobular liver necrosis associated with APAP. We have recently shown that dendritic cells (DCs) regulate intrahepatic inflammation in chronic liver disease and, therefore, postulated that DC may also modulate the hepatotoxic effects of APAP. We found that DC immune-phenotype was markedly altered after APAP challenge. In particular, liver DC expressed higher MHC II, costimulatory molecules, and Toll-like receptors, and produced higher interleukin (IL)-6, macrophage chemoattractant protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α). Conversely, spleen DC were unaltered. However, APAP-induced centrilobular necrosis, and its associated mortality, was markedly exacerbated upon DC depletion. Conversely, endogenous DC expansion using FMS-like tyrosine kinase 3 ligand (Flt3L) protected mice from APAP injury. Our mechanistic studies showed that APAP liver DC had the particular capacity to prevent NK cell activation and induced neutrophil apoptosis. Nevertheless, the exacerbated hepatic injury in DC-depleted mice challenged with APAP was independent of NK cells and neutrophils or numerous immune modulatory cytokines and chemokines. Conclusion: Taken together, these data indicate that liver DC protect against APAP toxicity, whereas their depletion is associated with exacerbated hepatotoxicity. (HEPATOLOGY 2011;)