2.50
Hdl Handle:
http://hdl.handle.net/10033/621208
Title:
RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury.
Authors:
Fischer, Julius C; Bscheider, Michael; Eisenkolb, Gabriel; Lin, Chia-Ching; Wintges, Alexander; Otten, Vera; Lindemans, Caroline A; Heidegger, Simon; Rudelius, Martina; Monette, Sébastien; Porosnicu Rodriguez, Kori A; Calafiore, Marco; Liebermann, Sophie; Liu, Chen; Lienenklaus, Stefan; Weiss, Siegfried; Kalinke, Ulrich ( 0000-0003-0503-9564 ) ; Ruland, Jürgen; Peschel, Christian; Shono, Yusuke; Docampo, Melissa; Velardi, Enrico; Jenq, Robert R; Hanash, Alan M; Dudakov, Jarrod A; Haas, Tobias; van den Brink, Marcel R M; Poeck, Hendrik
Abstract:
The 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.
Affiliation:
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Citation:
RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. 2017, 9 (386) Sci Transl Med
Journal:
Science translational medicine
Issue Date:
19-Apr-2017
URI:
http://hdl.handle.net/10033/621208
DOI:
10.1126/scitranslmed.aag2513
PubMed ID:
28424327
Type:
Article
Language:
en
ISSN:
1946-6242
Appears in Collections:
publications of the department of experimental infection research ([TC] EXPI)

Full metadata record

DC FieldValue Language
dc.contributor.authorFischer, Julius Cen
dc.contributor.authorBscheider, Michaelen
dc.contributor.authorEisenkolb, Gabrielen
dc.contributor.authorLin, Chia-Chingen
dc.contributor.authorWintges, Alexanderen
dc.contributor.authorOtten, Veraen
dc.contributor.authorLindemans, Caroline Aen
dc.contributor.authorHeidegger, Simonen
dc.contributor.authorRudelius, Martinaen
dc.contributor.authorMonette, Sébastienen
dc.contributor.authorPorosnicu Rodriguez, Kori Aen
dc.contributor.authorCalafiore, Marcoen
dc.contributor.authorLiebermann, Sophieen
dc.contributor.authorLiu, Chenen
dc.contributor.authorLienenklaus, Stefanen
dc.contributor.authorWeiss, Siegfrieden
dc.contributor.authorKalinke, Ulrichen
dc.contributor.authorRuland, Jürgenen
dc.contributor.authorPeschel, Christianen
dc.contributor.authorShono, Yusukeen
dc.contributor.authorDocampo, Melissaen
dc.contributor.authorVelardi, Enricoen
dc.contributor.authorJenq, Robert Ren
dc.contributor.authorHanash, Alan Men
dc.contributor.authorDudakov, Jarrod Aen
dc.contributor.authorHaas, Tobiasen
dc.contributor.authorvan den Brink, Marcel R Men
dc.contributor.authorPoeck, Hendriken
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.en
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

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