Hematopoietic stem cell transplantation (HSCT) is complicated by pulmonary infections that manifest post-transplantation. Despite engraftment, susceptibility to infection 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, TGFβ signaling post-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, DNMT 3a and DNMT 3b in AMs post-BMT. De novo DNMT 3a and 3b 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 EP2 antagonist abrogated the impaired bacterial killing. We also demonstrate that HSCT patients exhibit increased miR-29b; thus, these studies highlight miR-29b in driving defective AM responses and identify this miRNA and the EP2 antagonist as potential therapeutic targets.

Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.