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

• Published in: The Journal of clinical investigation 2009-11, Vol.119 (11), p.3213-3225
• Main Authors: Connolly, Michael K, Bedrosian, Andrea S, Mallen-St Clair, Jon, Mitchell, Aaron P, Ibrahim, Junaid, Stroud, Andrea, Pachter, H Leon, Bar-Sagi, Dafna, Frey, Alan B, Miller, George
• Format: Article
• Language: English
• Subjects: Animal models in research; Animals; Care and treatment; CD4-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - cytology; Cell Proliferation; Cytokines - metabolism; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - pathology; Fibrosis; Gene Expression Regulation - immunology; Genetic aspects; Health aspects; Inflammation - immunology; Inflammation - pathology; Interleukin-6 - metabolism; Killer Cells, Natural - metabolism; Liver - cytology; Liver - metabolism; Liver - pathology; Liver Cirrhosis - immunology; Liver Cirrhosis - pathology; Liver diseases; Lymph Nodes - cytology; Mice; Mice, Inbred C57BL; Phenotype; Risk factors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI37581

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-alpha. Therefore, modulating DC function may be an attractive approach to experimental therapeutics in fibro-inflammatory liver disease.