Research ArticleGraft-Versus-Host Disease

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

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Science Translational Medicine  19 Apr 2017:
Vol. 9, Issue 386, eaag2513
DOI: 10.1126/scitranslmed.aag2513

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A STING in the tail for GVHD

RIG-I/MAVS and cGAS/STING are innate recognition pathways that sense specific RNA or DNA patterns and induce IFN-I expression. Fischer et al. now show that endogenous and targeted activation of these pathways reduces intestinal injury after irradiation or chemotherapy and during graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Activation of RIG-I/MAVS and STING results in an IFN-I response that protects intestinal mucosal barrier function in vivo and promotes growth of intestinal organoids in vitro. IFN-I–mediated promotion of gut integrity correlates with attenuated graft-versus-host disease. Targeting these pathways may allow amelioration of intestinal tissue injury and regeneration of the intestinal stem cell niche.

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.

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