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Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.

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cam.issuedOnline2022-05-26
dc.contributor.authorYin, Kelvin
dc.contributor.authorPatten, Daniel
dc.contributor.authorGough, Sarah
dc.contributor.authorde Barros Gonçalves, Susana
dc.contributor.authorChan, Adelyne
dc.contributor.authorOlan, Ioana
dc.contributor.authorCassidy, Liam
dc.contributor.authorPoblocka, Marta
dc.contributor.authorZhu, Haoran
dc.contributor.authorLun, Aaron
dc.contributor.authorSchuijs, Martijn
dc.contributor.authorYoung, Andrew
dc.contributor.authorMartinez-Jimenez, Celia
dc.contributor.authorHalim, Timotheus YF
dc.contributor.authorShetty, Shishir
dc.contributor.authorNarita, Masashi
dc.contributor.authorHoare, Matthew
dc.contributor.orcidYin, Kelvin [0000-0003-2993-6374]
dc.contributor.orcidPatten, Daniel [0000-0002-8745-0578]
dc.contributor.orcidChan, Adelyne [0000-0003-2214-0306]
dc.contributor.orcidOlan, Ioana [0000-0003-0692-1831]
dc.contributor.orcidCassidy, Liam [0000-0002-9312-6256]
dc.contributor.orcidLun, Aaron [0000-0002-3564-4813]
dc.contributor.orcidYoung, Andrew [0000-0002-7522-5525]
dc.contributor.orcidMartinez-Jimenez, Celia [0000-0002-9534-6201]
dc.contributor.orcidShetty, Shishir [0000-0002-4729-2173]
dc.contributor.orcidNarita, Masashi [0000-0001-7764-577X]
dc.contributor.orcidHoare, Matthew [0000-0001-5990-9604]
dc.date.accessioned2022-06-29T19:48:00Z
dc.date.available2022-06-29T19:48:00Z
dc.date.issued2022-05-01
dc.date.updated2022-06-29T19:47:59Z
dc.descriptionFunder: National Institute for Health and Care Research
dc.descriptionFunder: Diabetes UK
dc.descriptionFunder: BIRAX
dc.description.abstractSenescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4+ T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS-ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.
dc.identifier.doi10.17863/CAM.85966
dc.identifier.eissn1549-5477
dc.identifier.issn0890-9369
dc.identifier.other35618311
dc.identifier.otherPMC9186388
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338553
dc.languageeng
dc.language.isoeng
dc.publisherCold Spring Harbor Laboratory
dc.publisher.urlhttp://dx.doi.org/10.1101/gad.349585.122
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1549-5477
dc.sourcenlmid: 8711660
dc.subjectNF-κB
dc.subjectSASP
dc.subjectendothelium
dc.subjectimmune surveillance
dc.subjectliver
dc.subjectsenescence
dc.subjectAnimals
dc.subjectCellular Senescence
dc.subjectEndothelial Cells
dc.subjectEndothelium
dc.subjectMice
dc.subjectNF-kappa B
dc.subjectPhenotype
dc.titleSenescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.
dc.typeArticle
dcterms.dateAccepted2022-05-16
prism.endingPage549
prism.issueIdentifier9-10
prism.publicationNameGenes Dev
prism.startingPage533
prism.volume36
pubs.funder-project-idCancer Research UK (CB4210)
pubs.funder-project-idCancer Research UK (19924)
pubs.funder-project-idMedical Research Council (MR/R010013/1)
pubs.funder-project-idCancer Research UK (via Newcastle University) (BH183441)
pubs.funder-project-idCancer Research UK (via Newcastle University) (BH172934)
pubs.funder-project-idCancer Research UK (C52489/A29681)
pubs.funder-project-idCancer Research UK (19924)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/S013466/1)
pubs.funder-project-idBBSRC (BB/T013486/1)
pubs.funder-project-idNational Institute for Health and Care Research (IS-BRC-1215-20014)
pubs.funder-project-idWellcome Trust (204622/Z/16/Z)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1101/gad.349585.122

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