Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice

Justin R. Henning, Christopher S. Graffeo, Adeel Rehman, Nina C. Fallon, Constantinos P. Zambirinis, Atsuo Ochi, Rocky Barilla, Mohsin Jamal, Michael Deutsch, Stephanie Greco, Melvin Ego-Osuala, Usama Bin-Saeed, Raghavendra S. Rao, Sana Badar, Juan P. Quesada, Devrim Acehan, George Miller

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)589-602
Number of pages14
JournalHepatology
Volume58
Issue number2
DOIs
StatePublished - Aug 1 2013

All Science Journal Classification (ASJC) codes

  • Hepatology

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    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., & Miller, G. (2013). Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology, 58(2), 589-602. https://doi.org/10.1002/hep.26267