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 |
| DOI/URL: | |
| Notes: | Sophie Lieberman's name is misspelled on the original publication -- Article -- Export Date: 2 June 2017 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work