In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α
Michael K. Connolly, … , Alan B. Frey, George Miller
Michael K. Connolly, … , Alan B. Frey, George Miller
Published October 12, 2009
Citation Information: J Clin Invest. 2009;119(11):3213-3225. https://doi.org/10.1172/JCI37581.
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Research Article Hepatology

In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α

Abstract

Hepatic fibrosis occurs during most chronic liver diseases and is driven by inflammatory responses to injured tissue. Because DCs are central to modulating liver immunity, we postulated that altered DC function contributes to immunologic changes in hepatic fibrosis and affects the pathologic inflammatory milieu within the fibrotic liver. Using mouse models, we determined the contribution of DCs to altered hepatic immunity in fibrosis and investigated the role of DCs in modulating the inflammatory environment within the fibrotic liver. We found that DC depletion completely abrogated the elevated levels of many inflammatory mediators that are produced in the fibrotic liver. DCs represented approximately 25% of the fibrotic hepatic leukocytes and showed an elevated CD11b+CD8– fraction, a lower B220+ plasmacytoid fraction, and increased expression of MHC II and CD40. Moreover, after liver injury, DCs gained a marked capacity to induce hepatic stellate cells, NK cells, and T cells to mediate inflammation, proliferation, and production of potent immune responses. The proinflammatory and immunogenic effects of fibrotic DCs were contingent on their production of TNF-α. Therefore, modulating DC function may be an attractive approach to experimental therapeutics in fibro-inflammatory liver disease.

Authors

Michael K. Connolly, Andrea S. Bedrosian, Jon Mallen-St. Clair, Aaron P. Mitchell, Junaid Ibrahim, Andrea Stroud, H. Leon Pachter, Dafna Bar-Sagi, Alan B. Frey, George Miller

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Figure 8

FLDCs activate HSCs.

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FLDCs activate HSCs. (A–D) HSCs were cultured alone or cocultured with D...
(A–D) HSCs were cultured alone or cocultured with DCs. At 24 hours, DCs were washed off, and HSCs were either (A) analyzed for surface marker expression by flow cytometry or (B–D) cultured alone for an additional 24 hours before analysis for inflammatory mediator production in conditioned media. (A) FLDCs induced higher HSC expression of CD40 and ICAM-1. (B and C) HSCs that had been cocultured with FLDCs produced elevated levels of numerous inflammatory mediators, whereas NLDCs only induced HSCs to produce higher KC (P < 0.05). Furthermore, CpG-treated FLDCs induced higher HSC production of IL-1α, IL-6, G-CSF, GMCSF, MIG, and MCP-1 compared with unstimulated FLDCs (P < 0.05). Conversely, priming NLDCs with CpG did not enhance their ability to activate HSCs. (D) To determine the mechanism of DC-HSC cross-talk, in selected experiments, cellular contact was prevented between HSCs and FLDCs by using 0.4-μm transwell inserts. Alternatively, TNF-α was blocked using 5 μg/ml 2E2. Prevention of cellular contact partially abrogated HSC production of IL-1α, MIP-1α, MIP-1β, IL-6, G-CSF, MIP-2, and KC (all P < 0.05). Similarly, TNF-α blockade reduced HSC production of all inflammatory mediators except MIP-1α (P < 0.05). (E) To test DC induction of HSC proliferation, irradiated DCs were coincubated with HSCs for 48 hours. Proliferation was measured by uptake of 3H-thymidine over the final 12 hours. FLDCs induced a 6-fold increase in HSC proliferation (P < 0.05). DC-HSC experiments were repeated at least twice.