Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice

TY - JOUR

T1 - Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice

AU - Pradere, Jean-Philippe

AU - Kluwe, Johannes

AU - De Minicis, Samuele

AU - Jiao, Jing-Jing

AU - Gwak, Geum-Youn

AU - Dapito, Dianne H

AU - Jang, Myoung-Kuk

AU - Günther, Nina Doreen

AU - Mederacke, Ingmar

AU - Friedman, Richard

AU - Dragomir, Ana-Cristina

AU - Aloman, Costica

AU - Schwabe, Robert F

N1 - Copyright © 2013 by the American Association for the Study of Liver Diseases.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - UNLABELLED: Although it is well established that hepatic macrophages play a crucial role in the development of liver fibrosis, the underlying mechanisms remain largely elusive. Moreover, it is not known whether other mononuclear phagocytes such as dendritic cells (DCs) contribute to hepatic stellate cell (HSC) activation and liver fibrosis. We show for the first time that hepatic macrophages enhance myofibroblast survival in a nuclear factor kappa B (NF-κB)-dependent manner and thereby promote liver fibrosis. Microarray and pathway analysis revealed no induction of HSC activation pathways by hepatic macrophages but a profound activation of the NF-κB pathway in HSCs. Conversely, depletion of mononuclear phagocytes during fibrogenesis in vivo resulted in suppressed NF-κB activation in HSCs. Macrophage-induced activation of NF-κB in HSCs in vitro and in vivo was mediated by interleukin (IL)-1 and tumor necrosis factor (TNF). Notably, IL-1 and TNF did not promote HSC activation but promoted survival of activated HSCs in vitro and in vivo and thereby increased liver fibrosis, as demonstrated by neutralization in coculture experiments and genetic ablation of IL-1 and TNF receptor in vivo. Coculture and in vivo ablation experiments revealed only a minor contribution to NF-κB activation in HSCs by DCs, and no contribution of DCs to liver fibrosis development, respectively.CONCLUSION: Promotion of NF-κB-dependent myofibroblast survival by macrophages but not DCs provides a novel link between inflammation and fibrosis.

AB - UNLABELLED: Although it is well established that hepatic macrophages play a crucial role in the development of liver fibrosis, the underlying mechanisms remain largely elusive. Moreover, it is not known whether other mononuclear phagocytes such as dendritic cells (DCs) contribute to hepatic stellate cell (HSC) activation and liver fibrosis. We show for the first time that hepatic macrophages enhance myofibroblast survival in a nuclear factor kappa B (NF-κB)-dependent manner and thereby promote liver fibrosis. Microarray and pathway analysis revealed no induction of HSC activation pathways by hepatic macrophages but a profound activation of the NF-κB pathway in HSCs. Conversely, depletion of mononuclear phagocytes during fibrogenesis in vivo resulted in suppressed NF-κB activation in HSCs. Macrophage-induced activation of NF-κB in HSCs in vitro and in vivo was mediated by interleukin (IL)-1 and tumor necrosis factor (TNF). Notably, IL-1 and TNF did not promote HSC activation but promoted survival of activated HSCs in vitro and in vivo and thereby increased liver fibrosis, as demonstrated by neutralization in coculture experiments and genetic ablation of IL-1 and TNF receptor in vivo. Coculture and in vivo ablation experiments revealed only a minor contribution to NF-κB activation in HSCs by DCs, and no contribution of DCs to liver fibrosis development, respectively.CONCLUSION: Promotion of NF-κB-dependent myofibroblast survival by macrophages but not DCs provides a novel link between inflammation and fibrosis.

KW - Animals

KW - Cell Survival

KW - Coculture Techniques

KW - Dendritic Cells

KW - Disease Models, Animal

KW - Gene Deletion

KW - Hepatic Stellate Cells

KW - Interleukin-1

KW - Liver

KW - Liver Cirrhosis

KW - Macrophages

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - NF-kappa B

KW - Receptors, Tumor Necrosis Factor

KW - Signal Transduction

U2 - 10.1002/hep.26429

DO - 10.1002/hep.26429

M3 - SCORING: Journal article

C2 - 23553591

VL - 58

SP - 1461

EP - 1473

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 4

ER -