title: Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice.
abstract: 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.
  
  
  CONCLUSIONS
  Promotion of NF-κB-dependent myofibroblast survival by macrophages but not DCs provides a novel link between inflammation and fibrosis.
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pradere
authors.forename: Johannes
authors.initials: J
authors.lastname: Kluwe
authors.forename: Samuele
authors.initials: S
authors.lastname: De Minicis
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Jiao
authors.forename: Geum-Youn
authors.initials: GY
authors.lastname: Gwak
authors.forename: Dianne H
authors.initials: DH
authors.lastname: Dapito
authors.forename: Myoung-Kuk
authors.initials: MK
authors.lastname: Jang
authors.forename: Nina D
authors.initials: ND
authors.lastname: Guenther
authors.forename: Ingmar
authors.initials: I
authors.lastname: Mederacke
authors.forename: Richard
authors.initials: R
authors.lastname: Friedman
authors.forename: Ana-Cristina
authors.initials: AC
authors.lastname: Dragomir
authors.forename: Costica
authors.initials: C
authors.lastname: Aloman
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000473:pathology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D055166:Hepatic Stellate Cells / Q000473:pathology*; D007375:Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000473:pathology* / Q000503:physiopathology*; D008264:Macrophages / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007375:Interleukin-1; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor
references.citation: Gastroenterology. 2006 Feb;130(2):435-52
references.pmid: 16472598
references.citation: Hepatology. 2009 Jul;50(1):261-74
references.pmid: 19554540
references.citation: Physiol Rev. 2008 Jan;88(1):125-72
references.pmid: 18195085
references.citation: Hepatology. 2012 Jan;55(1):244-55
references.pmid: 21898476
references.citation: Hepatology. 2011 Jan;53(1):230-42
references.pmid: 20979056
references.citation: Hepatology. 2003 Jan;37(1):87-95
references.pmid: 12500193
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Jul;281(1):G200-7
references.pmid: 11408273
references.citation: J Clin Invest. 2005 Feb;115(2):209-18
references.pmid: 15690074
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10663-8
references.pmid: 9380692
references.citation: Gastroenterology. 2009 Jun;136(7):2334-2344.e1
references.pmid: 19303015
references.citation: Oncogene. 2006 Oct 30;25(51):6800-16
references.pmid: 17072329
references.citation: PLoS One. 2010 Jun 10;5(6):e11049
references.pmid: 20548789
references.citation: Lancet. 2008 Mar 8;371(9615):838-51
references.pmid: 18328931
references.citation: Hepatology. 2006 Dec;44(6):1441-51
references.pmid: 17133483
references.citation: J Clin Invest. 1998 Aug 1;102(3):538-49
references.pmid: 9691091
references.citation: Nat Rev Gastroenterol Hepatol. 2011 Feb;8(2):108-18
references.pmid: 21293511
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9448-53
references.pmid: 22566629
references.citation: Gastroenterology. 2010 Jul;139(1):323-34.e7
references.pmid: 20347818
references.citation: Trends Immunol. 2007 Dec;28(12):525-31
references.pmid: 17964853
references.citation: Gastroenterology. 2007 May;132(5):1937-46
references.pmid: 17484886
references.citation: Apoptosis. 2005 Oct;10(5):927-39
references.pmid: 16151628
references.citation: Hepatol Res. 2003 Feb;25(2):180-191
references.pmid: 12644055
references.citation: Gastroenterology. 2005 Jan;128(1):108-20
references.pmid: 15633128
references.citation: J Immunol. 2007 Apr 15;178(8):5288-95
references.pmid: 17404313
references.citation: J Clin Invest. 2005 Nov;115(11):3072-82
references.pmid: 16276416
references.citation: Hepatology. 2006 Dec;44(6):1487-501
references.pmid: 17133487
references.citation: Semin Liver Dis. 2001 Aug;21(3):417-26
references.pmid: 11586469
references.citation: Nat Med. 2007 Nov;13(11):1324-32
references.pmid: 17952090
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):E3186-95
references.pmid: 23100531
references.citation: Annu Rev Immunol. 2009;27:147-63
references.pmid: 19302037
references.citation: J Clin Invest. 2005 Jan;115(1):56-65
references.pmid: 15630444
references.citation: Gastroenterology. 2010 Jan;138(1):347-59
references.pmid: 19782079
references.citation: Gastroenterology. 2009 Aug;137(2):713-23
references.pmid: 19375424
references.citation: Nat Med. 2006 Jun;12(6):671-6
references.pmid: 16715087
references.citation: J Clin Invest. 2009 Nov;119(11):3213-25
references.pmid: 19855130
references.citation: Nat Methods. 2012 Feb 26;9(4):385-90
references.pmid: 22367054
references.citation: Hepatology. 2011 Jun;53(6):2003-15
references.pmid: 21433043
references.citation: Hepatology. 2003 Feb;37(2):267-76
references.pmid: 12540776
references.citation: Gut. 2012 Jun;61(6):885-93
references.pmid: 22198715
references.citation: Hepatology. 2011 Jul;54(1):319-27
references.pmid: 21523796
references.citation: Hepatology. 2012 Nov;56(5):1902-12
references.pmid: 22544759
references.citation: Science. 1998 Sep 11;281(5383):1680-3
references.pmid: 9733516
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Jun;296(6):G1324-31
references.pmid: 19342509