DNA sensor associated type I Interferon signalling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids

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dc.contributor.authorFlood, Peter
dc.contributor.authorFanning, Aine
dc.contributor.authorWoznicki, Jerzy A.
dc.contributor.authorCrowley, Tadhg
dc.contributor.authorChristopher, Andrea
dc.contributor.authorVaccaro, Alessandra
dc.contributor.authorHouston, Aileen M.
dc.contributor.authorMcSweeney, Sheila
dc.contributor.authorRoss, Sarah
dc.contributor.authorHogan, Aileen
dc.contributor.authorBrint, Aileen
dc.contributor.authorSkowyra, Agnieszka
dc.contributor.authorBustamante, Milan
dc.contributor.authorAmbrose, Monica
dc.contributor.authorMoloney, Gerard M.
dc.contributor.authorMacSharry, John
dc.contributor.authorHammarström, Marie-Louise
dc.contributor.authorHurley, Margot
dc.contributor.authorFitzgibbons, Christine
dc.contributor.authorQuigley, Eamonn M. M.
dc.contributor.authorShanahan, Fergus
dc.contributor.authorZulquernain, Syed A.
dc.contributor.authorMcCarthy, Jane
dc.contributor.authorDodson, G. Steven
dc.contributor.authorDabbagh, Karim
dc.contributor.authorMcRae, Bradford L.
dc.contributor.authorMelgar, Silvia
dc.contributor.authorNally, Ken
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderSecond Genomeen
dc.date.accessioned2022-10-03T11:22:54Z
dc.date.available2022-10-03T11:22:54Z
dc.date.issued2022-09-27
dc.date.updated2022-10-03T10:57:11Z
dc.description.abstractDNA sensor pathways can initiate inflammasome, cell death and type I interferon (IFN) signalling in immune-mediated inflammatory diseases (IMIDs); including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC); by analysing expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n=31), inactive UC (n=31), active UC (n=33) and a UC single cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ and TNF-α on gene expression, cytokine production and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLRP3, caspase or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1β/IL-18/CXCL10. The expression of DNA sensor pathway genes - PYHIN family members (AIM2, IFI16, MNDA, PYHIN1), as well as ZBP1, cGAS and DDX41 were increased in active UC and expressed in a cell type restricted pattern. Inflammasome genes (CASP1, IL1B, IL18), type I IFN inducers (STING, TBK1, IRF3), IFNB1 and type I IFN biomarker genes (OAS2, IFIT2, MX2) were also increased in active UC. Co-treatment of organoids with IFN-β or IFN-γ and TNFα increased expression of IFI16, ZBP1, CASP1, cGAS and STING, induced cell death and IL-1β/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationFlood, P., Fanning, A., Woznicki, J. A., Crowley, T., Christopher, A., Vaccaro, A., Houston, A., McSweeney, S., Ross, S., Hogan, A., Brint, A., Skowyra, A., Bustamante, M., Ambrose, M., Moloney, G. M., MacSharry, J., Hammarström, M.-L., Hurley, M., Fitzgibbons, C., Quigley, E. M. M., Shanahan, F., Zulquernain, S. A., McCarthy, J., Dodson, G. S., Dabbagh, K., McRae, B. L., Melgar, S. and Nally, K. (2022) 'DNA sensor associated type I Interferon signalling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids', American Journal of Physiology - Gastrointestinal and Liver Physiology. doi: 10.1152/ajpgi.00104.2022en
dc.identifier.doi10.1152/ajpgi.00104.2022en
dc.identifier.eissn1522-1547
dc.identifier.issn0193-1857
dc.identifier.journaltitleAmerican Journal of Physiology - Gastrointestinal and Liver Physiologyen
dc.identifier.urihttps://hdl.handle.net/10468/13724
dc.language.isoenen
dc.publisherAmerican Physiological Societyen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2273/IE/Alimentary Pharmabiotic Centre (APC) - Interfacing Food & Medicine/en
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Spokes Programme/14/SP/2710/IE/Gut Inflammation _ Discovery and Therapeutic Targeting of the Secretome-Receptome Inflammatory Network in Inflammatory Bowel Disease/en
dc.rights© 2022, American Physiological Society. All rights reserved. This is a post-peer-review, pre-copyedit version of an article published in American Journal of Physiology - Gastrointestinal and Liver Physiology. The final authenticated version is available online at: https://doi.org/10.1152/ajpgi.00104.2022en
dc.subjectUlcerative colitisen
dc.subjectEpitheliumen
dc.subjectInterferonen
dc.subjectInflammasomeen
dc.subjectJAK inhibitoren
dc.titleDNA sensor associated type I Interferon signalling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoidsen
dc.typeArticle (peer-reviewed)en
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