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 1

Hepatic fibrosis alters the composition of liver NPC and DC phenotype.

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Hepatic fibrosis alters the composition of liver NPC and DC phenotype. (...
(A) The liver surface contour of TAA/leptin-treated mice was markedly irregular. (B) H&E examination of the livers of treated mice revealed a distorted hepatic architectural pattern. Regenerative nodules were seen (asterisks), bounded by fibrous septa (arrows). In addition, there was diffuse ductal proliferation (arrowheads). Masson trichrome and picric acid–Sirius red staining highlighted the collagen network surrounding and bridging the portal triads. Original magnification, ×10 (H&E and Masson trichrome); ×20 (picric acid–Sirius red). (C–E) Liver NPCs were analyzed by flow cytometry. The percentage of cells within selected gates is indicated. (C) Density plots of NPCs from normal and fibrotic liver. CD11c+ DCs increased in fibrotic livers. In addition, a CD11chi subpopulation expanded in fibrotic livers (arrow), which was rare in controls. Gr1+CD11b+ myeloid-derived cells and CD3+CD8+ T cells were also dramatically expanded in fibrotic livers. (D) DC subset analysis revealed a lower CD11c+B220+ plasmacytoid fraction and a higher CD11b+CD8– fraction among FLDCs compared with NLDCs. (E) Liver CD11c+ cells were assayed for expression of DC surface markers. Histograms show that freshly isolated FLDCs were more mature than controls. (F) FACS-sorted CD11c+ DCs were cultured for 24 hours either alone or with supplemental CpG before analysis for MHC II expression by flow cytometry. Median fluorescence is shown. There was considerably higher MHC II expression in FLDCs compared with NLDCs (P < 0.05). Isotype staining was similar for both groups (not shown). Phenotypic studies were repeated 4 times.