Transforming growth factor-β induces microRNA-29b to promote murine alveolar macrophage dysfunction after bone marrow transplantation

Domingo-Gonzalez, Racquel; Wilke, Carol A.; Laouar, Yasmina; Brown, Jeanette P.; Freeman, Christine M.; Curtis, Jeffrey L.; Yanik, Gregory A.; Moore, Bethany B.

doi:10.1152/ajplung.00283.2014

Cited by 22 publications

(21 citation statements)

References 62 publications

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“…Thus, it is likely that the conditioning regimen followed by an infectious stimulus is necessary to drive full elaboration of the Th17 response. In this regard, we have previously shown that lung epithelial cells are potent producers of TGFβ post-BMT, further, CD11c+ cells isolated from γHV-68 infected BMT mice secrete pro-Th17 cytokines such as IL-6, IL-23, and TGFβ which could help promote robust Th17 responses 27 , 40 .…”

Section: Discussionmentioning

confidence: 95%

Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to γ-herpesvirus infection

et al. 2018

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Idiopathic pneumonia syndrome (IPS) is a common, often fatal, complication following hematopoietic stem cell transplantation (HSCT) characterized by severe pneumonitis and interstitial fibrosis. Fully reconstituted syngeneic bone marrow transplant (BMT) mice infected with murine gammaherpesvirus (γHV-68) develop IL-17-driven pneumonitis and fibrosis which mimics clinical manifestations of IPS. We found CD103+ and CD11b+ dendritic cells (DCs) are selectively deficient for the Notch ligand, DLL4, following BMT and CD4+ T-cells isolated from lungs and spleens of infected BMT mice display Notch signaling defects. Mice transplanted with CD4-Cre-driven dominant-negative Notch transcriptional regulator Mastermind Like (CCD mice) bone marrow displayed elevated IL-17 and TGFβ in the lungs, a further expansion of Th17 cells, and developed more fibrosis than WT-BMT mice. Culture of BMT lung leukocytes with recombinant Notch ligand, DLL4, restored Notch signaling and decreased production of IL-17. Adoptive transfer of CD11c+ DCs could restore Th1 and limit Th17 in WT-BMT but not CCD-BMT mice indicating a specific DC / CD4+ T-cell Notch interaction modulates IL-17 production following reconstitution in syngeneic BMT mice. Given recent clinical observations showing that patients with pulmonary complications post-transplant harbor occult herpesvirus infections, these data provide mechanistic insight and suggest potential therapies for these devastating conditions.

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Section: Discussionmentioning

confidence: 95%

Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to γ-herpesvirus infection

et al. 2018

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“…TGF-␤1 is an important modulator of T cell differentiation (17) and has been shown to antagonize DNMT1 accumulation in T cells (60), where DNMT1 plays a critical role in T cell development (61). In alveolar macrophages, we previously showed that TGF-␤1 increased the expression of DNMT1 by inhibiting expression of microRNA-29b (62). microRNA-148b and microRNA-152 have also been shown to inhibit DNMT1 The mean densitometric values of phosphorylated GSK-3␤ from seven independent experiments are shown below a representative immunoblot.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β1 Increases DNA Methyltransferase 1 and 3a Expression through Distinct Post-transcriptional Mechanisms in Lung Fibroblasts

Koh

Scruggs

Huang

2016

Journal of Biological Chemistry

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DNA methylation is a fundamental epigenetic mark that plays a critical role in differentiation and is mediated by the actions of DNA methyltransferases (DNMTs). TGF-β1 is one of the most potent inducers of fibroblast differentiation, and although many of its actions on fibroblasts are well described, the ability of TGF-β1 to modulate DNA methylation in mesenchymal cells is less clear. Here, we examine the ability of TGF-β1 to modulate the expression of various DNMTs in primary lung fibroblasts (CCL210). TGF-β1 increased the protein expression, but not RNA levels, of both DNMT1 and DNMT3a. The increases in DNMT1 and DNMT3a were dependent on TGF-β1 activation of focal adhesion kinase and PI3K/Akt. Activation of mammalian target of rapamycin complex 1 by Akt resulted in increased protein translation of DNMT3a. In contrast, the increase in DNMT1 by TGF-β1 was not dependent on new protein synthesis and instead was due to decreased protein degradation. TGF-β1 treatment led to the phosphorylation and inactivation of glycogen synthase kinase-3β, which resulted in inhibition of DNMT1 ubiquitination and proteosomal degradation. The phosphorylation and inactivation of glycogen synthase kinase-3β was dependent on mammalian target of rapamycin complex 1. These results demonstrate that TGF-β1 increases expression of DNMT1 and DNMT3a through different post-transcriptional mechanisms. Because DNA methylation is critical to many processes including development and differentiation, for which TGF-β1 is known to be crucial, the ability of TGF-β1 to increase expression of both DNMT1 and DNMT3a demonstrates a novel means by which TGF-β1 may regulate DNA methylation in these cells.

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“…miR-29b is another miRNA whose expression in MΦs has been reported to be upregulated by TGF-β. Furthermore, this has been linked to the defective functioning of MΦs after bone marrow transplantation ( 89 ). Here, miR-29b upregulates COX-2 expression via indirect means resulting in MΦs with lesser bactericidal activity.…”

Section: Anti-inflammatory Polarizationmentioning

confidence: 99%

MicroRNA: Dynamic Regulators of Macrophage Polarization and Plasticity

et al. 2017

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The ability of a healthy immune system to clear the plethora of antigens it encounters incessantly relies on the enormous plasticity displayed by the comprising cell types. Macrophages (MΦs) are crucial member of the mononuclear phagocyte system (MPS) that constantly patrol the peripheral tissues and are actively recruited to the sites of injury and infection. In tissues, infiltrating monocytes replenish MΦ. Under the guidance of the local micro-milieu, MΦ can be activated to acquire specialized functional phenotypes. Similar to T cells, functional polarization of macrophage phenotype viz., inflammatory (M1) and reparative (M2) is proposed. Equipped with diverse toll-like receptors (TLRs), these cells of the innate arm of immunity recognize and phagocytize antigens and secrete cytokines that activate the adaptive arm of the immune system and perform key roles in wound repair. Dysregulation of MΦ plasticity has been associated with various diseases and infection. MicroRNAs (miRNAs) have emerged as critical regulators of transcriptome output. Their importance in maintaining health, and their contribution toward disease, encompasses virtually all aspects of human biology. Our understanding of miRNA-mediated regulation of MΦ plasticity and polarization can be utilized to modulate functional phenotypes to counter their role in the pathogenesis of numerous disease, including cancer, autoimmunity, periodontitis, etc. Here, we provide an overview of current knowledge regarding the role of miRNA in shaping MΦ polarization and plasticity through targeting of various pathways and genes. Identification of miRNA biomarkers of diagnostic/prognostic value and their therapeutic potential by delivery of miRNA mimics or inhibitors to dynamically alter gene expression profiles in vivo is highlighted.

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Transforming growth factor-β induces microRNA-29b to promote murine alveolar macrophage dysfunction after bone marrow transplantation

Cited by 22 publications

References 62 publications

Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to γ-herpesvirus infection

Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to γ-herpesvirus infection

Transforming Growth Factor-β1 Increases DNA Methyltransferase 1 and 3a Expression through Distinct Post-transcriptional Mechanisms in Lung Fibroblasts

MicroRNA: Dynamic Regulators of Macrophage Polarization and Plasticity

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