title: Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis.
abstract: Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix components, ultimately leading to fibrosis and liver failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33's profibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.
authors: Medical Department 1, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors: Tamar
authors: T
authors: McHedlidze
authors: Maximilian
authors: M
authors: Waldner
authors: Steffen
authors: S
authors: Zopf
authors: Jennifer
authors: J
authors: Walker
authors: Andrew L
authors: AL
authors: Rankin
authors: Marcus
authors: M
authors: Schuchmann
authors: David
authors: D
authors: Voehringer
authors: Andrew N J
authors: AN
authors: McKenzie
authors: Markus F
authors: MF
authors: Neurath
authors: Stefan
authors: S
authors: Pflanz
authors: Stefan
authors: S
authors: Wirtz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D055166:Hepatic Stellate Cells / Q000378:metabolism; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000276:immunology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053659:Receptors, Interleukin-4, Type II / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D053659:Receptors, Interleukin-4, Type II; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse
references: Cytokine. 2008 Jun;42(3):358-64
references: 18450470
references: J Leukoc Biol. 2009 Oct;86(4):769-78
references: 19451398
references: J Hepatol. 2010 Sep;53(3):519-27
references: 20579762
references: J Parasitol. 2010 Oct;96(5):900-7
references: 20950096
references: Eur J Immunol. 2011 Jun;41(6):1675-86
references: 21469105
references: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10913-8
references: 18667700
references: Nat Immunol. 2012 Jan 22;13(3):229-36
references: 22267218
references: Eur J Immunol. 2011 Aug;41(8):2341-8
references: 21557213
references: Nat Immunol. 2011 May 29;12(7):631-8
references: 21623379
references: Nature. 2010 Apr 29;464(7293):1367-70
references: 20200518
references: J Immunol. 2010 Sep 15;185(6):3472-80
references: 20693421
references: Semin Liver Dis. 2010 Aug;30(3):215-25
references: 20665374
references: Int Immunol. 2011 May;23(5):307-15
references: 21422152
references: Gastroenterology. 2008 May;134(6):1655-69
references: 18471545
references: Sci Signal. 2008 Dec 23;1(51):pe55
references: 19109238
references: Nat Immunol. 2011 Sep 11;12(11):1055-62
references: 21909091
references: Immunity. 2009 Jul 17;31(1):84-98
references: 19559631
references: Clin Rheumatol. 2011 Jun;30(6):825-30
references: 21246230
references: Nature. 2010 Apr 29;464(7293):1362-6
references: 20200520
references: Hepatology. 2011 Jan;53(1):219-29
references: 21140473
references: Immunity. 2010 Sep 24;33(3):364-74
references: 20817571
references: J Cell Mol Med. 2010 Jun;14(6B):1726-39
references: 19508382
references: Gastroenterology. 1996 Mar;110(3):821-31
references: 8608892
references: Nat Rev Immunol. 2010 Feb;10(2):103-10
references: 20081870
references: Nat Immunol. 2011 Nov;12(11):1045-54
references: 21946417
references: Nat Rev Rheumatol. 2011 Jun;7(6):321-9
references: 21519352
references: Trends Immunol. 2009 May;30(5):227-33
references: 19359217
references: Curr Opin Allergy Clin Immunol. 2011 Apr;11(2):109-14
references: 21301328
references: J Clin Invest. 2009 Jul;119(7):1858-70
references: 19603542
references: Nat Rev Gastroenterol Hepatol. 2010 Aug;7(8):425-36
references: 20585339
references: Nat Immunol. 2011 Oct 09;12(11):1071-7
references: 21983833
references: Immunity. 2012 Oct 19;37(4):634-48
references: 23063333
references: Trends Immunol. 2010 Nov;31(11):407-13
references: 20951092
references: Gene Ther. 1999 Jul;6(7):1258-66
references: 10455434
references: J Clin Invest. 2005 Feb;115(2):209-18
references: 15690074
references: Immunity. 2012 May 25;36(5):821-33
references: 22608496
references: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18581-6
references: 20937871
references: Immunity. 2001 Aug;15(2):303-11
references: 11520464
references: Nature. 2010 Jan 28;463(7280):540-4
references: 20023630
references: J Allergy Clin Immunol. 2012 Jan;129(1):191-8.e1-4
references: 22079492
references: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11489-94
references: 20534524
references: J Immunol. 2010 Feb 1;184(3):1526-35
references: 20042577
references: J Immunol. 2007 Aug 15;179(4):2551-5
references: 17675517
references: J Immunol. 2012 Feb 1;188(3):1503-13
references: 22198948
references: Z Gastroenterol. 2007 Jan;45(1):43-50
references: 17236120
references: J Hepatol. 2012 Jan;56(1):26-33
references: 21703183
references: Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9021-6
references: 19439663
references: Immunity. 2005 Nov;23(5):479-90
references: 16286016
references: Methods Enzymol. 2003;373:3-16
references: 14714393
references: J Immunol. 2011 Sep 1;187(5):2814-23
references: 21804025
references: Cytokine Growth Factor Rev. 2006 Jun;17(3):173-88
references: 16540365