| First Author | Domingo-Gonzalez R | Year | 2015 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 308 |
| Issue | 1 | Pages | L86-95 |
| PubMed ID | 25361568 | Mgi Jnum | J:227805 |
| Mgi Id | MGI:5702825 | Doi | 10.1152/ajplung.00283.2014 |
| Citation | Domingo-Gonzalez R, et al. (2015) Transforming growth factor-beta induces microRNA-29b to promote murine alveolar macrophage dysfunction after bone marrow transplantation. Am J Physiol Lung Cell Mol Physiol 308(1):L86-95 |
| abstractText | 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-beta (TGF-beta) 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-beta 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. |
