title: MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD.
abstract: Acute graft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic cell transplantation (allo-HCT); therefore, a better understanding of its biology may improve therapeutic options. We observed miR-146a up-regulation in T cells of mice developing acute GVHD compared with untreated mice. Transplanting miR-146a(-/-) T cells caused increased GVHD severity, elevated tumor necrosis factor (TNF) serum levels, and reduced survival. TNF receptor-associated factor 6 (TRAF6), a verified target of miR-146a, was up-regulated in miR-146a(-/-) T cells following alloantigen stimulation. Higher TRAF6 levels translated into increased nuclear factor-κB activity and TNF production in miR-146a(-/-) T cells. Conversely, the detrimental effect of miR-146a deficiency in T cells was antagonized by TNF blockade, whereas phytochemical induction of miR-146a or its overexpression using a miR-146a mimic reduced GVHD severity. In humans, the minor genotype of the single nucleotide polymorphism rs2910164 in HCT donors, which reduces expression of miR-146a, was associated with severe acute GVHD (grade III/IV). We show that miR-146a functions as a negative regulator of donor T cells in GVHD by targeting TRAF6, leading to reduced TNF transcription. Because miR-146a expression can be exogenously enhanced, our results provide a novel targeted molecular approach to mitigate GVHD.
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Spemann Graduate School of Biology and Medicine, and Faculty of Biology, Albert Ludwigs University Freiburg, Freiburg, Germany;
authors.forename: Natalie
authors.initials: N
authors.lastname: Stickel
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Prinz
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Department of Medicine, Clinic for Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Hasselblatt
authors.affiliation: Department of Pathology, Freiburg University Medical Center, Albert Ludwigs University Freiburg, Freiburg, Germany;
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center.
authors.forename: Marie
authors.initials: M
authors.lastname: Follo
authors.affiliation: Department of Medicine, Clinic for Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Finke
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center.
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.affiliation: Center for Chronic Immunodeficiency, Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany; and.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Centre for Biological Signaling Studies, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000818:Animals; D017353:Gene Deletion; D006086:Graft vs Host Disease / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D013601:T-Lymphocytes / Q000378:metabolism* / Q000637:transplantation; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha