These authors contributed equally to this work.
Steatohepatitis/Metabolic Liver Disease
Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice
Article first published online: 24 JUN 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 58, Issue 2, pages 589–602, August 2013
How to Cite
Henning, J. R., Graffeo, C. S., Rehman, A., Fallon, N. C., Zambirinis, C. P., Ochi, A., Barilla, R., Jamal, M., Deutsch, M., Greco, S., Ego-Osuala, M., Bin-Saeed, U., Rao, R. S., Badar, S., Quesada, J. P., Acehan, D. and Miller, G. (2013), Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology, 58: 589–602. doi: 10.1002/hep.26267
Potential conflict of interest: Nothing to report.
This work was supported, in part, by a Liver Scholar Award from the American Liver Foundation (to G.M.) and National Institutes of Health Awards 1UL1RR029893 (to J.R.H.), DK085278 (to G.M.), and CA155649 (to G.M.).
See Editorial on Page 494
- Issue published online: 29 JUL 2013
- Article first published online: 24 JUN 2013
- Accepted manuscript online: 15 JAN 2013 03:09PM EST
- Manuscript Accepted: 21 DEC 2012
- Manuscript Received: 4 JUN 2012
Nonalcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DCs) are antigen-presenting cells with an emerging role in hepatic inflammation. We postulated that DCs are important in the progression of NASH. We found that intrahepatic DCs expand and mature in NASH liver and assume an activated immune phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibroinflammation. Our mechanistic studies support a regulatory role for DCs in NASH by limiting sterile inflammation through their role in the clearance of apoptotic cells and necrotic debris. We found that DCs limit CD8+ T-cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. Conclusion: Our findings support a role for DCs in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH. (HEPATOLOGY 2013;58:589–602)