Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation

Benjamin D. Singer, Jason R. Mock, Neil R. Aggarwal, Brian T. Garibaldi, Venkataramana K. Sidhaye, Marcus A. Florez, Eric Chau, Kevin W. Gibbs, Pooja Mandke, Ashutosh Tripathi, Srinivasan Yegnasubramanian, Landon S. King, Franco R. D'Alessio

Research output: Contribution to journalArticlepeer-review

Abstract

Acute respiratory distress syndrome (ARDS) is a common and often fatal inflammatory lung condition without effective targeted therapies. Regulatory T cells (Tregs) resolve lung inflammation, but mechanisms that enhance Tregs to promote resolution of established damage remain unknown. DNA demethylation at the forkhead box protein 3 (Foxp3) locus and other key Treg loci typify the Treg lineage. To test how dynamic DNA demethylation affects lung injury resolution, we administered the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) to wild-type (WT) mice beginning 24 hours after intratracheal LPS-induced lung injury. Mice that received DAC exhibited accelerated resolution of their injury. Lung CD4+CD25hi Foxp3+ Tregs from D AC-treated WT mice increased in number and displayed enhanced Foxp3 expression, activation state, suppressive phenotype, and proliferative capacity. Lymphocyte-deficient recombinase activating gene-1-null mice and Treg-depleted (diphtheria toxin-treated Foxp3DTR) mice did not resolve their injury in response to DAC. Adoptive transfer of 2 ×105 DAC-treated, but not vehicle-treated, exogenous Tregs rescued Treg-deficient mice from ongoing lung inflammation. In addition, in WT mice with influenza-induced lung inflammation, DAC rescue treatment facilitated recovery of their injury and promoted an increase in lung Treg number. Thus, DNA methyltransferase inhibition, at least in part, augments Treg number and function to accelerate repair of experimental lung injury. Epigenetic pathways represent novel manipulable targets for the treatment of ARDS.

Original languageEnglish (US)
Pages (from-to)641-652
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume52
Issue number5
DOIs
StatePublished - May 1 2015

Keywords

  • 5-aza-2' deoxycytidine
  • Acute lung injury
  • DNA methylation
  • Epigenetics
  • Foxp3

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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