title: MicroRNA-155-deficient dendritic cells cause less severe GVHD through reduced migration and defective inflammasome activation.
abstract: The successful treatment of acute leukemias with allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (GVHD). Because microRNA-155 (miR-155) regulates activation of the innate immune system, we aimed to determine its function in dendritic cells (DCs) during GVHD in an experimental model. We observed that miR-155 deficiency of the recipient led to improved survival, reduced serum levels of proinflammatory cytokines, and lower GVHD histopathology scores. In addition, miR-155(-/-) bone marrow chimeric mice receiving allo-HCT and miR-155(-/-) DCs showed that miR-155 deficiency in the DC compartment was responsible for protection from GVHD. Activated miR-155(-/-) DCs displayed lower expression of various purinergic receptors and impaired migration toward adenosine triphosphate (ATP). Microarray analysis of lipopolysaccharide/ATP-stimulated miR-155(-/-) DCs revealed mitogen-activated protein kinase pathway dysregulation and reduced inflammasome-associated gene expression. Consistent with this gene expression data, we observed reduced ERK activation, caspase-1 cleavage, and IL-1β production in miR-155(-/-) DCs. The connection between miR-155 and inflammasome activation was supported by the fact that Nlrp3/miR-155 double-knockout allo-HCT recipient mice had no increased protection from GVHD compared with Nlrp3(-/-) recipients. This study indicates that during GVHD, miR-155 promotes DC migration toward sites of ATP release accompanied by inflammasome activation. Inhibiting proinflammatory miR-155 by antagomir treatment could help reduce this complication of allo-HCT.
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center.
authors.forename: Sophia
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center.
authors.forename: Benjamin A H
authors.identifier: http://orcid.org/0000-0001-8802-416X
authors.initials: BA
authors.lastname: Smith
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center.
authors.forename: Joseena
authors.initials: J
authors.lastname: Iype
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prestipino
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Department of Cardiology and Angiology I, Heart Center, University of Freiburg.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grundmann
authors.affiliation: Department of Pathology.
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.affiliation: Department of Pneumology, Freiburg University Medical Center, and.
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Beck
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Prinz
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Finke
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center.
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Centre for Biological Signalling Studies BIOSS, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000502:physiology; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D058847:Inflammasomes; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse