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dc.contributor.authorFischer, Julius C
dc.contributor.authorBscheider, Michael
dc.contributor.authorEisenkolb, Gabriel
dc.contributor.authorLin, Chia-Ching
dc.contributor.authorWintges, Alexander
dc.contributor.authorOtten, Vera
dc.contributor.authorLindemans, Caroline A
dc.contributor.authorHeidegger, Simon
dc.contributor.authorRudelius, Martina
dc.contributor.authorMonette, Sébastien
dc.contributor.authorPorosnicu Rodriguez, Kori A
dc.contributor.authorCalafiore, Marco
dc.contributor.authorLiebermann, Sophie
dc.contributor.authorLiu, Chen
dc.contributor.authorLienenklaus, Stefan
dc.contributor.authorWeiss, Siegfried
dc.contributor.authorKalinke, Ulrich
dc.contributor.authorRuland, Jürgen
dc.contributor.authorPeschel, Christian
dc.contributor.authorShono, Yusuke
dc.contributor.authorDocampo, Melissa
dc.contributor.authorVelardi, Enrico
dc.contributor.authorJenq, Robert R
dc.contributor.authorHanash, Alan M
dc.contributor.authorDudakov, Jarrod A
dc.contributor.authorHaas, Tobias
dc.contributor.authorvan den Brink, Marcel R M
dc.contributor.authorPoeck, Hendrik
dc.date.accessioned2017-12-18T13:51:01Z
dc.date.available2017-12-18T13:51:01Z
dc.date.issued2017-04-19
dc.identifier.citationRIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. 2017, 9 (386) Sci Transl Meden
dc.identifier.issn1946-6242
dc.identifier.pmid28424327
dc.identifier.doi10.1126/scitranslmed.aag2513
dc.identifier.urihttp://hdl.handle.net/10033/621208
dc.description.abstractThe molecular pathways that regulate the tissue repair function of type I interferon (IFN-I) during acute tissue damage are poorly understood. We describe a protective role for IFN-I and the RIG-I/MAVS signaling pathway during acute tissue damage in mice. Mice lacking mitochondrial antiviral-signaling protein (MAVS) were more sensitive to total body irradiation- and chemotherapy-induced intestinal barrier damage. These mice developed worse graft-versus-host disease (GVHD) in a preclinical model of allogeneic hematopoietic stem cell transplantation (allo-HSCT) than did wild-type mice. This phenotype was not associated with changes in the intestinal microbiota but was associated with reduced gut epithelial integrity. Conversely, targeted activation of the RIG-I pathway during tissue injury promoted gut barrier integrity and reduced GVHD. Recombinant IFN-I or IFN-I expression induced by RIG-I promoted growth of intestinal organoids in vitro and production of the antimicrobial peptide regenerating islet-derived protein 3 γ (RegIIIγ). Our findings were not confined to RIG-I/MAVS signaling because targeted engagement of the STING (stimulator of interferon genes) pathway also protected gut barrier function and reduced GVHD. Consistent with this, STING-deficient mice suffered worse GVHD after allo-HSCT than did wild-type mice. Overall, our data suggest that activation of either RIG-I/MAVS or STING pathways during acute intestinal tissue injury in mice resulted in IFN-I signaling that maintained gut epithelial barrier integrity and reduced GVHD severity. Targeting these pathways may help to prevent acute intestinal injury and GVHD during allogeneic transplantation.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAdaptor Proteins, Signal Transducingen
dc.subject.meshAnimalsen
dc.subject.meshDEAD Box Protein 58en
dc.subject.meshGraft vs Host Diseaseen
dc.subject.meshHematopoietic Stem Cell Transplantationen
dc.subject.meshInterferon Type Ien
dc.subject.meshIntestinesen
dc.subject.meshMembrane Proteinsen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMice, Knockouten
dc.subject.meshNeutrophil Infiltrationen
dc.subject.meshOrganoidsen
dc.subject.meshPolymerase Chain Reactionen
dc.subject.meshSignal Transductionen
dc.subject.meshTransplantation, Homologousen
dc.titleRIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury.en
dc.typeArticleen
dc.contributor.departmentTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.en
dc.identifier.journalScience translational medicineen
refterms.dateFOA2018-06-13T21:28:30Z
html.description.abstractThe molecular pathways that regulate the tissue repair function of type I interferon (IFN-I) during acute tissue damage are poorly understood. We describe a protective role for IFN-I and the RIG-I/MAVS signaling pathway during acute tissue damage in mice. Mice lacking mitochondrial antiviral-signaling protein (MAVS) were more sensitive to total body irradiation- and chemotherapy-induced intestinal barrier damage. These mice developed worse graft-versus-host disease (GVHD) in a preclinical model of allogeneic hematopoietic stem cell transplantation (allo-HSCT) than did wild-type mice. This phenotype was not associated with changes in the intestinal microbiota but was associated with reduced gut epithelial integrity. Conversely, targeted activation of the RIG-I pathway during tissue injury promoted gut barrier integrity and reduced GVHD. Recombinant IFN-I or IFN-I expression induced by RIG-I promoted growth of intestinal organoids in vitro and production of the antimicrobial peptide regenerating islet-derived protein 3 γ (RegIIIγ). Our findings were not confined to RIG-I/MAVS signaling because targeted engagement of the STING (stimulator of interferon genes) pathway also protected gut barrier function and reduced GVHD. Consistent with this, STING-deficient mice suffered worse GVHD after allo-HSCT than did wild-type mice. Overall, our data suggest that activation of either RIG-I/MAVS or STING pathways during acute intestinal tissue injury in mice resulted in IFN-I signaling that maintained gut epithelial barrier integrity and reduced GVHD severity. Targeting these pathways may help to prevent acute intestinal injury and GVHD during allogeneic transplantation.


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