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

Fischer, Julius C; Bscheider, Michael; Eisenkolb, Gabriel; Lin, Chia-Ching; Wintges, Alexander; Otten, Vera; Lindemans, Caroline A; Heidegger, Simon; Rudelius, Martina; Monette, Sébastien; Porosnicu Rodriguez, Kori A; Calafiore, Marco; Liebermann, Sophie; Liu, Chen; Lienenklaus, Stefan; Weiss, Siegfried; Kalinke, Ulrich; Ruland, Jürgen; Peschel, Christian; Shono, Yusuke; Docampo, Melissa; Velardi, Enrico; Jenq, Robert R; Hanash, Alan M; Dudakov, Jarrod A; Haas, Tobias; van den Brink, Marcel R M; Poeck, Hendrik     «

Fischer, Julius C; Bscheider, Michael; Eisenkolb, Gabriel; Lin, Chia-Ching; Wintges, Alexander; Otten, Vera; Lindemans, Caroline A; Heidegger, Simon; Rudelius, Martina; Monette, Sébastien; Porosnicu Rodriguez, Kori A; Calafiore, Marco; Liebermann, Sophie; Liu, Chen; Lienenklaus, Stefan; Weiss, Siegfried; Kalinke, Ulrich; Ruland, Jürgen; Peschel, Christian; Shono, Yusuke; Docampo, Melissa; Velardi, Enrico; Jenq, Robert R; Hanash, Alan M; Dudakov, Jarrod A; Haas, Tobias; van den Brink, Marcel R M;...     »

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 ? (RegIII?). 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.     «

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...     »