Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice
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Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. / Pradere, Jean-Philippe; Kluwe, Johannes; De Minicis, Samuele; Jiao, Jing-Jing; Gwak, Geum-Youn; Dapito, Dianne H; Jang, Myoung-Kuk; Günther, Nina Doreen; Mederacke, Ingmar; Friedman, Richard; Dragomir, Ana-Cristina; Aloman, Costica; Schwabe, Robert F.
in: HEPATOLOGY, Jahrgang 58, Nr. 4, 01.10.2013, S. 1461-73.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -