TNF-α synergises with IFN-γ to induce caspase-8-JAK1/2-STAT1-dependent death of intestinal epithelial cells.
Apoptosis
Biopsy
Caspase 8
/ metabolism
Cell Death
Cell Line, Tumor
Colon
/ pathology
Cytoprotection
Epithelial Cells
/ metabolism
Humans
Interferon-gamma
/ metabolism
Intestines
/ pathology
Janus Kinase 1
/ metabolism
Janus Kinase 2
/ metabolism
Mitochondria
/ metabolism
Organoids
/ pathology
RNA Interference
Receptors, Tumor Necrosis Factor, Type I
/ metabolism
STAT1 Transcription Factor
/ metabolism
Signal Transduction
Tumor Necrosis Factor-alpha
/ metabolism
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
23 09 2021
23 09 2021
Historique:
received:
08
02
2021
accepted:
08
09
2021
revised:
16
08
2021
entrez:
24
9
2021
pubmed:
25
9
2021
medline:
4
2
2022
Statut:
epublish
Résumé
Rewiring of host cytokine networks is a key feature of inflammatory bowel diseases (IBD) such as Crohn's disease (CD). Th1-type cytokines-IFN-γ and TNF-α-occupy critical nodes within these networks and both are associated with disruption of gut epithelial barrier function. This may be due to their ability to synergistically trigger the death of intestinal epithelial cells (IECs) via largely unknown mechanisms. In this study, through unbiased kinome RNAi and drug repurposing screens we identified JAK1/2 kinases as the principal and nonredundant drivers of the synergistic killing of human IECs by IFN-γ/TNF-α. Sensitivity to IFN-γ/TNF-α-mediated synergistic IEC death was retained in primary patient-derived intestinal organoids. Dependence on JAK1/2 was confirmed using genetic loss-of-function studies and JAK inhibitors (JAKinibs). Despite the presence of biochemical features consistent with canonical TNFR1-mediated apoptosis and necroptosis, IFN-γ/TNF-α-induced IEC death was independent of RIPK1/3, ZBP1, MLKL or caspase activity. Instead, it involved sustained activation of JAK1/2-STAT1 signalling, which required a nonenzymatic scaffold function of caspase-8 (CASP8). Further modelling in gut mucosal biopsies revealed an intercorrelated induction of the lethal CASP8-JAK1/2-STAT1 module during ex vivo stimulation of T cells. Functional studies in CD-derived organoids using inhibitors of apoptosis, necroptosis and JAKinibs confirmed the causative role of JAK1/2-STAT1 in cytokine-induced death of primary IECs. Collectively, we demonstrate that TNF-α synergises with IFN-γ to kill IECs via the CASP8-JAK1/2-STAT1 module independently of canonical TNFR1 and cell death signalling. This non-canonical cell death pathway may underpin immunopathology driven by IFN-γ/TNF-α in diverse autoinflammatory diseases such as IBD, and its inhibition may contribute to the therapeutic efficacy of anti-TNFs and JAKinibs.
Identifiants
pubmed: 34556638
doi: 10.1038/s41419-021-04151-3
pii: 10.1038/s41419-021-04151-3
pmc: PMC8459343
doi:
Substances chimiques
Receptors, Tumor Necrosis Factor, Type I
0
STAT1 Transcription Factor
0
Tumor Necrosis Factor-alpha
0
Interferon-gamma
82115-62-6
Janus Kinase 1
EC 2.7.10.2
Janus Kinase 2
EC 2.7.10.2
Caspase 8
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
864Subventions
Organisme : Wellcome Trust
ID : 110371/Z/15/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S021205/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 24387
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/T002824/1
Pays : United Kingdom
Organisme : Science Foundation Ireland (SFI)
ID : SFI-14/SP/2710
Organisme : Science Foundation Ireland (SFI)
ID : SFI-13/CDA/2171
Organisme : Science Foundation Ireland (SFI)
ID : SFI-12/RC/2273
Organisme : Medical Research Council
ID : G0400302
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
Références
Gastroenterology. 2019 Jan;156(1):275-278
pubmed: 30267714
Mol Ther. 2020 Apr 8;28(4):1078-1091
pubmed: 32053770
Mol Cell. 2020 Nov 5;80(3):396-409.e6
pubmed: 33108759
Biochim Biophys Acta. 2009 Apr;1788(4):864-71
pubmed: 18952050
Nature. 2012 Nov 1;491(7422):119-24
pubmed: 23128233
Cell Death Differ. 2017 Apr;24(4):660-671
pubmed: 28186502
J Biol Chem. 2011 Nov 11;286(45):39632-43
pubmed: 21937453
J Immunol. 2003 Dec 1;171(11):6164-72
pubmed: 14634132
Nat Rev Drug Discov. 2016 May;15(5):348-66
pubmed: 26775689
Sci Immunol. 2019 Dec 6;4(42):
pubmed: 31811055
Proc Natl Acad Sci U S A. 1983 Sep;80(17):5397-401
pubmed: 6193516
Nat Rev Mol Cell Biol. 2014 Feb;15(2):135-47
pubmed: 24452471
Gut. 2013 Jul;62(7):1062-71
pubmed: 22689519
J Immunol. 1996 Aug 1;157(3):1261-70
pubmed: 8757634
Cell Death Dis. 2020 Jan 27;11(1):68
pubmed: 31988296
Cell Death Differ. 2014 Aug;21(8):1229-39
pubmed: 24769733
Immunology. 1993 Jan;78(1):127-31
pubmed: 8436398
Nat Immunol. 2004 Feb;5(2):199-207
pubmed: 14730360
Nature. 2007 Mar 29;446(7135):557-61
pubmed: 17361131
J Biol Chem. 1999 Jun 11;274(24):17193-201
pubmed: 10358077
Mol Cell. 2017 Feb 16;65(4):730-742.e5
pubmed: 28212753
Nature. 2011 Sep 14;477(7364):335-9
pubmed: 21921917
Nature. 2014 Sep 4;513(7516):95-9
pubmed: 25186904
J Exp Med. 2014 Jun 30;211(7):1393-405
pubmed: 24980747
Nat Rev Immunol. 2014 May;14(5):329-42
pubmed: 24751956
J Mol Biol. 2007 Jun 15;369(4):967-84
pubmed: 17475277
Nature. 2014 Sep 4;513(7516):90-4
pubmed: 25132550
Nature. 2015 Jan 15;517(7534):311-20
pubmed: 25592536
J Exp Med. 2018 Nov 5;215(11):2868-2886
pubmed: 30254094
J Exp Med. 2010 Jul 5;207(7):1513-23
pubmed: 20530205
Clin Exp Immunol. 1991 Jan;83(1):79-84
pubmed: 1899066
Mol Cell Biol. 2000 Jul;20(13):4505-12
pubmed: 10848577
Mol Cell. 2017 Feb 16;65(4):715-729.e5
pubmed: 28212752
Nat Med. 2019 Apr;25(4):690-700
pubmed: 30936544
Inflamm Bowel Dis. 2020 Feb 11;26(3):407-422
pubmed: 31751457
Cell. 2009 Jun 12;137(6):1100-11
pubmed: 19524512
PLoS One. 2013 May 17;8(5):e63583
pubmed: 23691072
Gut. 1999 Aug;45(2):191-8
pubmed: 10403730
Cell Rep. 2017 Apr 25;19(4):785-797
pubmed: 28445729
Gastroenterology. 2013 Dec;145(6):1369-79
pubmed: 24036366
Immunity. 1994 Oct;1(7):553-62
pubmed: 7600284
Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16497-16506
pubmed: 31346084
Nat Commun. 2015 Apr 30;6:7002
pubmed: 25926053
Cell Mol Gastroenterol Hepatol. 2020;9(2):295-312
pubmed: 31606566
JCI Insight. 2018 Sep 20;3(18):
pubmed: 30232288
Dis Colon Rectum. 2003 Nov;46(11):1498-507
pubmed: 14605569
Nature. 2019 Nov;575(7784):683-687
pubmed: 31748744
J Clin Invest. 2018 Aug 1;128(8):3265-3279
pubmed: 29746256
Mol Cancer Ther. 2021 Sep;20(9):1627-1639
pubmed: 34389694
Nat Commun. 2015 Jun 24;6:7515
pubmed: 26104484
Mol Cell. 2000 Dec;6(6):1389-99
pubmed: 11163212
Cell Signal. 2005 Dec;17(12):1516-32
pubmed: 15908180
Nat Rev Immunol. 2020 Jun;20(6):375-388
pubmed: 32132681
Cell Death Differ. 2017 Mar;24(3):481-491
pubmed: 28106882
Sci Rep. 2020 Jan 28;10(1):1310
pubmed: 31992798
Nat Protoc. 2016 Aug;11(8):1444-54
pubmed: 27414760
J Immunol. 2008 Jul 15;181(2):1143-52
pubmed: 18606667
Nature. 1986 Oct 30-Nov 5;323(6091):819-22
pubmed: 2430188
Cell Death Differ. 2019 Jan;26(1):4-13
pubmed: 30050058
Gut. 2017 Dec;66(12):2069-2079
pubmed: 27803115
J Immunol. 2001 Apr 1;166(7):4481-9
pubmed: 11254704
Gut. 2019 May;68(5):814-828
pubmed: 29848778
Gut. 2004 Sep;53(9):1295-302
pubmed: 15306588
Inflamm Bowel Dis. 1998 Nov;4(4):285-90
pubmed: 9836081
J Biol Chem. 2019 Aug 9;294(32):11994-12006
pubmed: 31217278
Diabetes. 2007 Oct;56(10):2561-8
pubmed: 17620422
J Clin Invest. 2016 Nov 1;126(11):4346-4360
pubmed: 27756058
Cell Death Differ. 2010 Apr;17(4):699-709
pubmed: 19851330
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
Oncogene. 2006 Jan 5;25(1):152-9
pubmed: 16186808
Science. 1997 Nov 28;278(5343):1630-2
pubmed: 9374464
Cell Mol Gastroenterol Hepatol. 2016 Sep 20;3(1):72-81
pubmed: 28174758
Pharmacol Ther. 2018 Dec;192:100-111
pubmed: 30048708
Cell. 2019 Sep 5;178(6):1493-1508.e20
pubmed: 31474370
PLoS One. 2013 Oct 24;8(10):e78021
pubmed: 24205071
Nat Rev Gastroenterol Hepatol. 2017 May;14(5):269-278
pubmed: 28144028
Nature. 2011 Jul 31;477(7364):330-4
pubmed: 21804564
Immunity. 2010 Mar 26;32(3):392-402
pubmed: 20303298
Nat Rev Gastroenterol Hepatol. 2020 Jun;17(6):323-337
pubmed: 32203403
Nat Rev Immunol. 2018 Sep;18(9):545-558
pubmed: 29921905
Gut. 2002 Sep;51(3):379-85
pubmed: 12171960
Mol Cell Biol. 2011 Jul;31(14):2934-46
pubmed: 21576359
Cell. 2021 Jan 7;184(1):149-168.e17
pubmed: 33278357
J Immunol. 2003 Nov 15;171(10):5313-9
pubmed: 14607933
Nat Med. 1998 Apr;4(4):408-14
pubmed: 9546785
J Immunol. 2019 Sep 1;203(5):1348-1355
pubmed: 31358656
Nature. 2019 Nov;575(7784):679-682
pubmed: 31723262
Clin Exp Immunol. 1999 May;116(2):238-45
pubmed: 10337013
Science. 2016 Apr 1;352(6281):aaf2154
pubmed: 27034377
Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):E3109-18
pubmed: 23898178