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 4

Adoptive transfer of DCs from livers of fibrotic mice activates NK cells in vivo.

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Adoptive transfer of DCs from livers of fibrotic mice activates NK cells...
DCs (1 × 105) were harvested from the livers of normal or fibrotic mice by FACS, incubated for 6 hours with 5 μM CpG, and then injected directly into the spleens of naive animals. At 18 hours, NK cells were harvested from the spleens of recipient mice, plated at a concentration of 1 × 106, and assayed for production of (A) IL-6 and IFN-γ, (B) MCP-1, and (C) MIP-1α and MIP-1β in 24-hour cultures. (A–C) NK cells harvested from mice that received adoptively transferred FLDCs produced elevated IFN-γ, IL-6, MCP-1, MIP-1α, and MIP-1β (all P < 0.05). (D) Alternatively, NK cells from recipient mouse spleens were analyzed for CD69 expression by flow cytometry. CD69 was expressed at modestly higher levels on NK cells harvested from spleens injected with FLDCs compared with controls. The shaded histogram represents isotype staining. Experiments were repeated 3 times with similar results.