Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation.

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(+)CD25(hi)Foxp3(+) 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 Foxp3(DTR)) mice did not resolve their injury in response to DAC. Adoptive transfer of 2 × 10(5) 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.

DOI: 10.1165/rcmb.2014-0327OC
05010020162017
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@article{Singer2015RegulatoryTC, title={Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation.}, author={Benjamin D Singer and Jason R. Mock and Neil Aggarwal and Brian T Garibaldi and Venkataramana K Sidhaye and Marcus A Florez and Eric Chau and Kevin W. Gibbs and Pooja Mandke and Ashutosh Tripathi and Srinivasan Thomas Yegnasubramanian and Landon S. King and Franco R. D'Alessio}, journal={American journal of respiratory cell and molecular biology}, year={2015}, volume={52 5}, pages={641-52} }