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Sci Transl Med. 2017 Apr 19;9(386). pii: eaag2513. doi: 10.1126/scitranslmed.aag2513.

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

Author information

1
III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
2
Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Pediatric Blood and Bone Marrow Transplant Program, University Medical Center Utrecht, Utrecht, Netherlands.
4
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Institute of Pathology, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.
6
Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Rockefeller University, and Weill Cornell Medical College, New York, NY 10065, USA.
7
Department of Pathology and Laboratory Medicine, New Jersey Medical School and Robert Wood Johnson Medical School, Rutgers University, Newark, NJ 08903, USA.
8
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
9
Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
10
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
11
German Cancer Consortium (DKTK), Heidelberg, Germany.
12
German Center for Infection Research (DZIF), partner site Munich, Munich, Germany.
13
Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. hendrik.poeck@tum.de m-van-den-brink@ski.mskcc.org.
14
III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. hendrik.poeck@tum.de m-van-den-brink@ski.mskcc.org.

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.

PMID:
28424327
PMCID:
PMC5604790
DOI:
10.1126/scitranslmed.aag2513
[Indexed for MEDLINE]
Free PMC Article

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