RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury.
dc.contributor.author | Fischer, Julius C | |
dc.contributor.author | Bscheider, Michael | |
dc.contributor.author | Eisenkolb, Gabriel | |
dc.contributor.author | Lin, Chia-Ching | |
dc.contributor.author | Wintges, Alexander | |
dc.contributor.author | Otten, Vera | |
dc.contributor.author | Lindemans, Caroline A | |
dc.contributor.author | Heidegger, Simon | |
dc.contributor.author | Rudelius, Martina | |
dc.contributor.author | Monette, Sébastien | |
dc.contributor.author | Porosnicu Rodriguez, Kori A | |
dc.contributor.author | Calafiore, Marco | |
dc.contributor.author | Liebermann, Sophie | |
dc.contributor.author | Liu, Chen | |
dc.contributor.author | Lienenklaus, Stefan | |
dc.contributor.author | Weiss, Siegfried | |
dc.contributor.author | Kalinke, Ulrich | |
dc.contributor.author | Ruland, Jürgen | |
dc.contributor.author | Peschel, Christian | |
dc.contributor.author | Shono, Yusuke | |
dc.contributor.author | Docampo, Melissa | |
dc.contributor.author | Velardi, Enrico | |
dc.contributor.author | Jenq, Robert R | |
dc.contributor.author | Hanash, Alan M | |
dc.contributor.author | Dudakov, Jarrod A | |
dc.contributor.author | Haas, Tobias | |
dc.contributor.author | van den Brink, Marcel R M | |
dc.contributor.author | Poeck, Hendrik | |
dc.date.accessioned | 2017-12-18T13:51:01Z | |
dc.date.available | 2017-12-18T13:51:01Z | |
dc.date.issued | 2017-04-19 | |
dc.identifier.citation | RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. 2017, 9 (386) Sci Transl Med | en |
dc.identifier.issn | 1946-6242 | |
dc.identifier.pmid | 28424327 | |
dc.identifier.doi | 10.1126/scitranslmed.aag2513 | |
dc.identifier.uri | http://hdl.handle.net/10033/621208 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject.mesh | Adaptor Proteins, Signal Transducing | en |
dc.subject.mesh | Animals | en |
dc.subject.mesh | DEAD Box Protein 58 | en |
dc.subject.mesh | Graft vs Host Disease | en |
dc.subject.mesh | Hematopoietic Stem Cell Transplantation | en |
dc.subject.mesh | Interferon Type I | en |
dc.subject.mesh | Intestines | en |
dc.subject.mesh | Membrane Proteins | en |
dc.subject.mesh | Mice | en |
dc.subject.mesh | Mice, Inbred C57BL | en |
dc.subject.mesh | Mice, Knockout | en |
dc.subject.mesh | Neutrophil Infiltration | en |
dc.subject.mesh | Organoids | en |
dc.subject.mesh | Polymerase Chain Reaction | en |
dc.subject.mesh | Signal Transduction | en |
dc.subject.mesh | Transplantation, Homologous | en |
dc.title | RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. | en |
dc.type | Article | en |
dc.contributor.department | TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany. | en |
dc.identifier.journal | Science translational medicine | en |
refterms.dateFOA | 2018-06-13T21:28:30Z | |
html.description.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. |