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.
Highlights
RIG-I belongs to the pattern recognition family of cytoplasmic RIG-I–like receptors
In an acute graft-versus-host disease (GVHD) model, where conditioning-associated intestinal damage is crucial for subsequent allogeneic T cell–mediated pathology, we observed that Mavs−/− recipients of allogeneic donor bone marrow (BM) and T cells had increased mortality compared to Mavs+/+ littermates (Fig. 1D)
Previous studies have proposed a protective function of IFN-I in the setting of allo-HSCT [32] and of stromal mitochondrial antiviralsignaling protein (MAVS) signaling in a dextran sodium sulfate (DSS)–induced mouse model of colitis [18], but the mechanisms by which IFN-I contributes to this protection remain ill defined
Summary
RIG-I belongs to the pattern recognition family of cytoplasmic RIG-I–like receptors. Its primary function is to detect double-stranded 5′-triphosphate RNA (3pRNA) during viral or bacterial infection [1,2,3]. The cytosolic DNA receptor cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) and its adapter protein STING (stimulator of interferon genes; TMEM173) recognize DNA in various contexts, for example, microbial DNA or nuclear DNA released into the cytosol by necrotic cells [4]. CGAS binds to double-stranded DNA (dsDNA) and catalyzes the formation of cyclic dinucleotides. The latter can form cGAMP that activates STING to trigger innate immune gene transcription and IFN-I production [4]. IFN-I produced by plasmacytoid dendritic cells (pDCs) promotes skin repair upon mechanical barrier disruption [9] and increases intestinal epithelial turnover and repair of chemically damaged tissue. Unlike chemical injury of intestinal mucosa, irradiation- or chemotherapyinduced intestinal barrier dysfunction is a problem clinically
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
