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 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.

• Authors: Julius C Fischer, Michael Bscheider, Gabriel Eisenkolb, Chia-Ching Lin, Alexander Wintges, Vera Otten, Caroline A Lindemans, Simon Heidegger, Martina Rudelius, Sébastien Monette, Kori A Porosnicu Rodriguez, Marco Calafiore, Sophie Liebermann, Chen Liu, Stefan Lienenklaus, Siegfried Weiss, Ulrich Kalinke, Jürgen Ruland, Christian Peschel, Yusuke Shono, Melissa Docampo, Enrico Velardi, Robert R Jenq, Alan M Hanash, Jarrod A Dudakov, Tobias Haas, Marcel R M van den Brink, Hendrik Poeck
• Journal: Science translational medicine (Sci Transl Med) Vol. 9 Issue 386 (04 19 2017) ISSN: 1946-6242 [Electronic] United States
• PMID: 28424327 (Publication Type: Journal Article)
• Copyright: Copyright © 2017, American Association for the Advancement of Science.

Chemical References

• Adaptor Proteins, Signal Transducing
• IPS-1 protein, mouse
• Interferon Type I
• Membrane Proteins
• Sting1 protein, mouse
• Ddx58 protein, mouse
• DEAD Box Protein 58

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• DEAD Box Protein 58 (genetics, metabolism)
• Graft vs Host Disease (immunology, metabolism)
• Hematopoietic Stem Cell Transplantation
• Interferon Type I (metabolism)
• Intestinal Mucosa (metabolism)
• Intestines (radiation effects)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophil Infiltration (physiology)
• Organoids (cytology, metabolism)
• Polymerase Chain Reaction
• Signal Transduction (physiology)
• Transplantation, Homologous