RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury Journal Article

Authors: Fischer, J. C.; Bscheider, M.; Eisenkolb, G.; Lin, C. C.; Wintges, A.; Otten, V.; Lindemans, C. A.; Heidegger, S.; Rudelius, M.; Monette, S.; Porosnicu Rodriguez, K. A.; Calafiore, M.; Liebermann, S.; Liu, C.; Lienenklaus, S.; Weiss, S.; Kalinke, U.; Ruland, J.; Peschel, C.; Shono, Y.; Docampo, M.; Velardi, E.; Jenq, R. R.; Hanash, A. M.; Dudakov, J. A.; Haas, T.; Van Den Brink, M. R. M.; Poeck, H.
Article Title: RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury
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 g (RegIIIg). 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. 2017 © The Authors.
Keywords: signal transduction; controlled study; protein expression; unclassified drug; interferon; drug efficacy; nonhuman; animal cell; mouse; animal tissue; animal experiment; animal model; in vivo study; in vitro study; radiation injury; whole body radiation; graft versus host reaction; single drug dose; allogeneic hematopoietic stem cell transplantation; radiosensitivity; intestine flora; ex vivo study; intestine injury; adaptor protein; retinoic acid inducible protein i; mitochondrial antiviral signaling protein; intestine epithelium; polypeptide antibiotic agent; immune mediated injury; rna derivative; sting protein; article; intestine mucosa permeability; 5' triphosphate rna; regenerating islet derived protein 3 gamma
Journal Title: Science Translational Medicine
Volume: 9
Issue: 386
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2017-04-19
Start Page: eaag2513
Language: English
DOI: 10.1126/scitranslmed.aag2513
PROVIDER: scopus
PUBMED: 28424327
PMCID: PMC5604790
Notes: Sophie Lieberman's name is misspelled on the original publication -- Article -- Export Date: 2 June 2017 -- Source: Scopus
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