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

Racquel Domingo-Gonzalez1, Carol A Wilke2, Steven K Huang2

  • 1Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan;

American Journal of Physiology. Lung Cellular and Molecular Physiology
|November 2, 2014
PubMed

Insights

Pulmonary infections after hematopoietic stem cell transplantation (HSCT) are linked to impaired alveolar macrophage (AM) function. MicroRNA-29b (miR-29b) drives this defect by upregulating cyclooxygenase-2 (COX-2), offering a potential therapeutic target.

Area of Science:

  • Immunology
  • Molecular Biology
  • Transplantation Science

Background:

  • Pulmonary infections are a significant complication following hematopoietic stem cell transplantation (HSCT), persisting even after engraftment.
  • Previous studies linked increased cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) to impaired alveolar macrophage (AM) function post-HSCT.
  • The mechanisms driving COX-2 overexpression in AMs after HSCT remained unclear.

Purpose of the Study:

  • To elucidate the mechanisms by which transforming growth factor-β (TGF-β) signaling leads to COX-2 overexpression in AMs after bone marrow transplantation (BMT).
  • To investigate the role of microRNA-29b (miR-29b) in regulating COX-2 expression and AM function post-BMT.
  • To assess the therapeutic potential of targeting miR-29b for restoring AM function in HSCT recipients.

Main Methods:

  • Utilized a murine bone marrow transplant (BMT) model.
  • Investigated the effects of TGF-β signaling on miR-29b and DNA methyltransferase (DNMT) expression in AMs.
  • Employed transient transfection of miR-29b and miR-29b inhibitors in AMs.
  • Assessed COX-2 promoter methylation and expression.
  • Evaluated bacterial-killing capacity of AMs and the effect of an E prostanoid receptor 2 antagonist.

Main Results:

  • TGF-β signaling post-BMT induces miR-29b and decreases DNMTs (DNMT1, DNMT3a, DNMT3b) in AMs.
  • miR-29b directly reduces DNMT3a and DNMT3b, leading to hypomethylation of the COX-2 promoter and increased COX-2 expression.
  • miR-29b-induced COX-2 upregulation impairs AM bacterial-killing function, which is dependent on increased PGE2 levels.
  • Inhibition of miR-29b rescues the bacterial-killing defect in BMT AMs.
  • Elevated miR-29b levels were observed in HSCT patients.

Conclusions:

  • miR-29b plays a critical role in driving defective AM responses post-HSCT by upregulating COX-2.
  • The miR-29b/DNMT/COX-2 pathway represents a novel mechanism contributing to post-transplant pulmonary infections.
  • Targeting miR-29b presents a promising therapeutic strategy to restore AM function and improve outcomes in HSCT patients.
Keywords:
alveolar macrophagebone marrow transplantationmicroRNA-29bprostaglandintransforming growth factor-β

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