title: Transforming growth factor-β induces microRNA-29b to promote murine alveolar macrophage dysfunction after bone marrow transplantation.
abstract: Hematopoietic stem cell transplantation (HSCT) is complicated by pulmonary infections that manifest posttransplantation. Despite engraftment, susceptibility to infections persists long after reconstitution. Previous work using a murine bone marrow transplant (BMT) model implicated increased cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in promoting impaired alveolar macrophage (AM) responses. However, mechanisms driving COX-2 overexpression remained elusive. Previously, transforming growth factor-β (TGF-β) signaling after BMT was shown to promote hypomethylation of the COX-2 gene. Here, we provide mechanistic insight into how this occurs and show that TGF-β induces microRNA (miR)-29b while decreasing DNA methyltransferases (DNMT)1, DNMT3a, and DNMT3b in AMs after BMT. De novo DNMT3a and DNMT3b were decreased upon transient transfection of miR-29b, resulting in decreased methylation of the COX-2 promoter and induction of COX-2. As a consequence, miR-29b-driven upregulation of COX-2 promoted AM dysfunction, and transfection of BMT AMs with a miR-29b inhibitor rescued the bacterial-killing defect. MiR-29b-mediated defects in BMT AMs were dependent on increased levels of PGE2, as miR-29b-transfected AMs treated with a novel E prostanoid receptor 2 antagonist abrogated the impaired bacterial killing. We also demonstrate that patients that have undergone HSCT exhibit increased miR-29b; thus these studies highlight miR-29b in driving defective AM responses and identify this miRNA as a potential therapeutic target.
authors.affiliation: Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan;
authors.forename: Racquel
authors.initials: R
authors.lastname: Domingo-Gonzalez
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan;
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wilke
authors.affiliation: Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan;
authors.forename: Steven K
authors.initials: SK
authors.lastname: Huang
authors.affiliation: Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan;
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Laouar
authors.affiliation: Research Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan;
authors.forename: Jeanette P
authors.initials: JP
authors.lastname: Brown
authors.affiliation: Research Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan;
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan; Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Medical Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan;
authors.forename: Jeffrey L
authors.identifier: http://orcid.org/0000-0001-5191-4847
authors.initials: JL
authors.lastname: Curtis
authors.affiliation: Department of Pediatrics, Division of Hematology-Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.affiliation: Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan; Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan; bmoore@umich.edu.
authors.forename: Bethany B
authors.identifier: http://orcid.org/0000-0003-3051-745X
authors.initials: BB
authors.lastname: Moore
mesh_terms: D000328:Adult; D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C547014:MIRN29 microRNA, mouse; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D015232:Dinoprostone
keywords: alveolar macrophage; bone marrow transplantation; microRNA-29b; prostaglandin; transforming growth factor-β