title: 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.
authors.affiliation: 1 Johns Hopkins University Division of Pulmonary and Critical Care Medicine; and.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Singer
authors.forename: Jason R
authors.initials: JR
authors.lastname: Mock
authors.forename: Neil R
authors.initials: NR
authors.lastname: Aggarwal
authors.forename: Brian T
authors.initials: BT
authors.lastname: Garibaldi
authors.forename: Venkataramana K
authors.initials: VK
authors.lastname: Sidhaye
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Florez
authors.forename: Eric
authors.initials: E
authors.lastname: Chau
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gibbs
authors.forename: Pooja
authors.initials: P
authors.lastname: Mandke
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathi
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Yegnasubramanian
authors.forename: Landon S
authors.initials: LS
authors.lastname: King
authors.forename: Franco R
authors.initials: FR
authors.lastname: D'Alessio
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000821:virology; D019264:Adoptive Transfer; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077209:Decitabine; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D053118:Influenza A Virus, H1N1 Subtype; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000821:virology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000637:transplantation / Q000821:virology; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D008070:Lipopolysaccharides; C482199:lipopolysaccharide, E coli O55-B5; C064658:RAG-1 protein; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine
keywords: 5-aza-2′-deoxycytidine; DNA methylation; Foxp3; acute lung injury; epigenetics