title: Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase.
abstract: DNA-dependent protein kinase (DNA-PK) mediates double-stranded DNA break repair, V(D)J recombination and immunoglobulin class switch recombination, as well as innate immune and pro-inflammatory responses. However, there is limited information regarding the role of DNA-PK in adaptive immunity mediated by dendritic cells (DCs), which are the primary antigen-presenting cells in allergic asthma. Here we show that house dust mite induces DNA-PK phosphorylation, which is a marker of DNA-PK activation, in DCs via the generation of intracellular reactive oxygen species. We also demonstrate that pharmacological inhibition of DNA-PK, as well as the specific deletion of DNA-PK in DCs, attenuates the induction of allergic sensitization and Th2 immunity via a mechanism that involves the impaired presentation of mite antigens. Furthermore, pharmacological inhibition of DNA-PK following antigen priming similarly reduces the manifestations of mite-induced airway disease. Collectively, these findings suggest that DNA-PK may be a potential target for treatment of allergic asthma.
authors.affiliation: Laboratory of Asthma and Lung Inflammation, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Amarjit
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Laboratory of Obesity and Aging Research, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Brown
authors.affiliation: Laboratory of Asthma and Lung Inflammation, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Xianglan
authors.initials: X
authors.lastname: Yao
authors.affiliation: Laboratory of Obesity and Aging Research, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Shutong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Laboratory of Obesity and Aging Research, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Sung-Jun
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Transgenic Core Facility, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Flow Cytometry Core Facility, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dagur
authors.affiliation: Flow Cytometry Core Facility, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: J Philip
authors.initials: JP
authors.lastname: McCoy
authors.affiliation: Animal Surgery and Resources Core Facility, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Keeran
authors.affiliation: Animal Surgery and Resources Core Facility, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Gayle Z
authors.initials: GZ
authors.lastname: Nugent
authors.affiliation: Animal Surgery and Resources Core Facility, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Jeffries
authors.affiliation: Pathology Core Facility, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Qu
authors.affiliation: Pathology Core Facility, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Zu-Xi
authors.initials: ZX
authors.lastname: Yu
authors.affiliation: Laboratory of Asthma and Lung Inflammation, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Stewart J
authors.initials: SJ
authors.lastname: Levine
authors.affiliation: Laboratory of Obesity and Aging Research, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Chung
mesh_terms: D056704:Adaptive Immunity; D000284:Administration, Oral; D000818:Animals; D017951:Antigen Presentation; D001249:Asthma / Q000276:immunology; D039521:CD11c Antigen / Q000378:metabolism; D002867:Chromones / Q000737:chemistry; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology; D005260:Female; D006967:Hypersensitivity / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009025:Morpholines / Q000737:chemistry; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D039981:Pyroglyphidae; D017382:Reactive Oxygen Species / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000469:parasitology
chemical_list: C499693:8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; D039521:CD11c Antigen; D002867:Chromones; D004268:DNA-Binding Proteins; D009025:Morpholines; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D007073:Immunoglobulin E; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse