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

作者：Julius Clemens Fischer, Michael Bscheider, Gabriel Eisenkolb, Chia-Ching Lin, Alexander Wintges, Vera Otten, Caroline A. Lindemans, Simon M 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 D. Docampo, Enrico Velardi, Robert R. Jenq, Alan M. Hanash, Jarrod A. Dudakov, Tobias L. Haas, Marcel R.M. van den Brink, Hendrik Poeck · 发表于：Science Translational Medicine · 年份：2017 · DOI：10.1126/scitranslmed.aag2513 · 被引用次数：142 · 研究领域：interferon and immune responses、Inflammasome and immune disorders、Immune Response and Inflammation

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...