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DNA-dependent protein kinase inhibition blocks asthma in mice and modulates human endothelial and CD4⁺ T-cell
Mohamed A Ghonim1, Kusma Pyakurel2, Jihang Ju2
1Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, La; Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Background:
We reported that DNA-dependent protein kinase (DNA-PK) is critical for the expression of nuclear factor κB-dependent genes in TNF-α-treated glioblastoma cells, suggesting an involvement in inflammatory diseases.
Objective:
We sought to investigate the role of DNA-PK in asthma.
Methods:
Cell culture and ovalbumin (OVA)- or house dust mite-based murine asthma models were used in this study.
Results:
DNA-PK was essential for monocyte adhesion to TNF-α-treated endothelial cells. Administration of the DNA-PK inhibitor NU7441 reduced airway eosinophilia, mucus hypersecretion, airway hyperresponsiveness, and OVA-specific IgE production in mice prechallenged with OVA. Such effects correlated with a marked reduction in lung vascular cell adhesion molecule 1 expression and production of several cytokines, including IL-4, IL-5, IL-13, eotaxin, IL-2, and IL-12 and the chemokines monocyte chemoattractant protein 1 and keratinocyte-derived chemokine, with a negligible effect on IL-10/IFN-γ production. DNA-PK inhibition by gene heterozygosity of the 450-kDa catalytic subunit of the kinase (DNA-PKcs(+/-)) also prevented manifestation of asthma-like traits. These results were confirmed in a chronic model of asthma by using house dust mite, a human allergen. Remarkably, such protection occurred without causing severe combined immunodeficiency. Adoptive transfer of TH2-skewed OT-II wild-type CD4(+) T cells reversed IgE and TH2 cytokine production but not airway hyperresponsiveness in OVA-challenged DNA-PKcs(+/-) mice. DNA-PK inhibition reduced IL-4, IL-5, IL-13, eotaxin, IL-8, and monocyte chemoattractant protein 1 production without affecting IL-2, IL-12, IFN-γ, and interferon-inducible protein 10 production in CD3/CD28-stimulated human CD4(+) T cells, potentially by blocking expression of Gata3. These effects occurred without significant reductions in T-cell proliferation. In mouse CD4(+) T cells in vitro DNA-PK inhibition severely blocked CD3/CD28-induced Gata3 and T-bet expression in CD4(+) T cells and prevented differentiation of TH1 and TH2 cells under respective TH1- and TH2-skewing conditions.
Conclusion:
Our results suggest DNA-PK as a novel determinant of asthma and a potential target for the treatment of the disease.
Insights
DNA-dependent protein kinase (DNA-PK) plays a crucial role in asthma development by regulating inflammatory responses and T-cell differentiation. Inhibiting DNA-PK offers a potential therapeutic strategy for treating asthma without causing immunodeficiency.
Area of Science:
- Immunology
- Molecular Biology
- Respiratory Medicine
Background:
- DNA-dependent protein kinase (DNA-PK) is implicated in inflammatory diseases, particularly in nuclear factor κB-dependent gene expression.
- Previous findings suggest a potential role for DNA-PK in inflammatory processes.
Purpose of the Study:
- To investigate the specific role of DNA-PK in the pathogenesis of asthma.
- To explore DNA-PK as a potential therapeutic target for asthma treatment.
Main Methods:
- Utilized cell culture techniques and established murine models of asthma induced by ovalbumin (OVA) and house dust mite (HDM).
- Administered the DNA-PK inhibitor NU7441 and employed gene heterozygosity of DNA-PK catalytic subunit (DNA-PKcs(+/-)).
- Analyzed immune cell responses, cytokine production, and T-cell differentiation in vitro and in vivo.
Main Results:
- DNA-PK inhibition significantly reduced asthma symptoms, including airway eosinophilia, mucus production, and hyperresponsiveness.
- Treatment decreased the expression of adhesion molecules (VCAM-1) and key inflammatory cytokines (IL-4, IL-5, IL-13, eotaxin) and chemokines.
- DNA-PK inhibition in T cells blocked Gata3 expression, hindering TH1/TH2 differentiation without impairing T-cell proliferation or causing severe combined immunodeficiency.
Conclusions:
- DNA-dependent protein kinase (DNA-PK) is identified as a novel determinant in asthma pathogenesis.
- Targeting DNA-PK presents a promising therapeutic avenue for managing asthma and related inflammatory airway diseases.
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