Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase

Amarjit Mishra, Alexandra L. Brown, Xianglan Yao, Shutong Yang, Sung-Jun Park, Chengyu Liu, Pradeep K. Dagur, J. Philip McCoy, Karen J. Keeran, Gayle Z. Nugent, Kenneth R. Jeffries, Xuan Qu, Zu-Xi Yu, Stewart J. Levine () and Jay H. Chung ()
Additional contact information
Amarjit Mishra: Laboratory of Asthma and Lung Inflammation, NHLBI, NIH
Alexandra L. Brown: Laboratory of Obesity and Aging Research, NHLBI, NIH
Xianglan Yao: Laboratory of Asthma and Lung Inflammation, NHLBI, NIH
Shutong Yang: Laboratory of Obesity and Aging Research, NHLBI, NIH
Sung-Jun Park: Laboratory of Obesity and Aging Research, NHLBI, NIH
Chengyu Liu: Transgenic Core Facility, NHLBI, NIH
Pradeep K. Dagur: Flow Cytometry Core Facility, NHLBI, NIH
J. Philip McCoy: Flow Cytometry Core Facility, NHLBI, NIH
Karen J. Keeran: Animal Surgery and Resources Core Facility, NHLBI, NIH
Gayle Z. Nugent: Animal Surgery and Resources Core Facility, NHLBI, NIH
Kenneth R. Jeffries: Animal Surgery and Resources Core Facility, NHLBI, NIH
Xuan Qu: Pathology Core Facility, NHLBI, NIH
Zu-Xi Yu: Pathology Core Facility, NHLBI, NIH
Stewart J. Levine: Laboratory of Asthma and Lung Inflammation, NHLBI, NIH
Jay H. Chung: Laboratory of Obesity and Aging Research, NHLBI, NIH

Nature Communications, 2015, vol. 6, issue 1, 1-18

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7224

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