Journal Article

Regulatory T Cell DNA Methyltransferase Inhibition Accelerates Resolution of Lung Inflammation

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

2015

Overview

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+CD25hiFoxp3+ Tregs from DAC-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.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Acute Lung Injury - chemically induced / Acute Lung Injury - drug therapy / Acute Lung Injury - enzymology / Acute Lung Injury - immunology / Acute Lung Injury - virology / Adoptive Transfer / Animals / Azacitidine - analogs & derivatives / Azacitidine - pharmacology / CD25 antigen / CD4 antigen / Cells, Cultured / Chemotaxis, Leukocyte / Decitabine / Demethylation / Diphtheria / Diphtheria toxin / Disease Models, Animal / DNA damage / DNA methylation / DNA methyltransferase / DNA Modification Methylases - antagonists & inhibitors / DNA Modification Methylases - metabolism / Enzyme Inhibitors - pharmacology / Epigenetics / Forkhead protein / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / Foxp3 protein / Genes / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Immunoregulation / Inflammation / Influenza A Virus, H1N1 Subtype / Lipopolysaccharides / Lung - drug effects / Lung - enzymology / Lung - immunology / Lung - virology / Lungs / Lymphocytes / Lymphocytes T / Mice, Inbred C57BL / Mice, Knockout / Original Research / Phenotype / Phenotypes / Pneumonia - chemically induced / Pneumonia - drug therapy / Pneumonia - enzymology / Pneumonia - immunology / Pneumonia - virology / Recombinase / Respiratory distress syndrome / Rodents / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - enzymology / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - transplantation / T-Lymphocytes, Regulatory - virology / Time Factors / Trachea