In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α
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
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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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 2

DCs control the inflammatory milieu in liver fibrosis.

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DCs control the inflammatory milieu in liver fibrosis. (A) Freshly isola...
(A) Freshly isolated liver DCs were cultured for 24 hours at a concentration of 1 × 106. FLDCs produced more than 2-fold elevation in TNF-α compared with controls (P < 0.05). TNF-α production was further enhanced as a result of TLR9 ligation, but not TLR3, TLR4, or TLR5 ligation. (B) Similarly, FLDCs also produced elevated levels of IL-6 (P < 0.05). (C–E) NPCs were harvested from the livers of normal and fibrotic mice and cultured for 24 hours at a concentration of 1 × 106. Depletion of DCs from fibrotic NPC concentrates by FACS abrogated their elevated cytokine and chemokine production (P < 0.05 for each inflammatory mediator). (F) Freshly isolated NPCs from unmanipulated CD11c-DTR mice, fibrotic CD11c-DTR mice, or fibrotic CD11c-DTR mice that were depleted of DCs for 48 hours immediately prior to sacrifice were cultured as above. Cell culture supernatant was then assayed for inflammatory mediators. DC depletion in vivo in fibrotic mice markedly decreased NPC cytokine and chemokine production (P < 0.05 for each inflammatory mediator).