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

Fischer JC, Bscheider M, Eisenkolb G, Lin CC, Wintges A, Otten V, Lindemans CA, Heidegger S, Rudelius M, Monette S, Rodriguez KAP, Calafiore M, Liebermann S, Liu C, Lienenklaus S, Weiss S, Kalinke U, Ruland J, Peschel C, Shono Y, Docampo M, Velardi E, Jenq RR, Hanash AM, Dudakov JA, Haas T, Van Den Brink MRM, Poeck H (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 9

Article Number: eaag2513

Journal Issue: 386

DOI: 10.1126/scitranslmed.aag2513

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

Involved external institutions

Technische Universität München (TUM) DE Germany (DE) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Julius-Maximilians-Universität Würzburg DE Germany (DE) Rockefeller University US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) Rutgers, The State University of New Jersey US United States (USA) (US) Zentrum für Experimentelle und Klinische Infektionsforschung GmbH (TWINCORE) DE Germany (DE) Helmholtz-Zentrum für Infektionsforschung (HZI) DE Germany (DE)

How to cite

APA:

Fischer, J.C., Bscheider, M., Eisenkolb, G., Lin, C.-C., Wintges, A., Otten, V.,... Poeck, H. (2017). RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. Science Translational Medicine, 9(386). https://doi.org/10.1126/scitranslmed.aag2513

MLA:

Fischer, Julius C., et al. "RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury." Science Translational Medicine 9.386 (2017).

BibTeX: Download