Oxidized CaMKII promotes asthma through the activation of mast cells
Jingjing Qu, Danh C. Do, Yufeng Zhou, Elizabeth Luczak, Wayne Mitzner, Mark E. Anderson, Peisong Gao
Jingjing Qu, Danh C. Do, Yufeng Zhou, Elizabeth Luczak, Wayne Mitzner, Mark E. Anderson, Peisong Gao
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Research Article Immunology Pulmonology

Oxidized CaMKII promotes asthma through the activation of mast cells

Abstract

Oxidation of calmodulin-dependent protein kinase II (ox-CaMKII) by ROS has been associated with asthma. However, the contribution of ox-CaMKII to the development of asthma remains to be fully characterized. Here, we tested the effect of ox-CaMKII on IgE-mediated mast cell activation in an allergen-induced mouse model of asthma using oxidant-resistant CaMKII MMVVδ knockin (MMVVδ) mice. Compared with WT mice, the allergen-challenged MMVVδ mice displayed less airway hyperresponsiveness (AHR) and inflammation. These MMVVδ mice exhibited reduced levels of ROS and diminished recruitment of mast cells to the lungs. OVA-activated bone marrow–derived mast cells (BMMCs) from MMVVδ mice showed a significant inhibition of ROS and ox-CaMKII expression. ROS generation was dependent on intracellular Ca2+ concentration in BMMCs. Importantly, OVA-activated MMVVδ BMMCs had suppressed degranulation, histamine release, leukotriene C4, and IL-13 expression. Adoptive transfer of WT, but not MMVVδ, BMMCs, reversed the alleviated AHR and inflammation in allergen-challenged MMVVδ mice. The CaMKII inhibitor KN-93 significantly suppressed IgE-mediated mast cell activation and asthma. These studies support a critical but previously unrecognized role of ox-CaMKII in mast cells that promotes asthma and suggest that therapies to reduce ox-CaMKII may be a novel approach for asthma.

Authors

Jingjing Qu, Danh C. Do, Yufeng Zhou, Elizabeth Luczak, Wayne Mitzner, Mark E. Anderson, Peisong Gao

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Figure 7

Adoptive transfer of WT mast cells reverses the protective effect of CaMKII MMVVδ in a mouse model of asthma.

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Adoptive transfer of WT mast cells reverses the protective effect of CaM...
(A) Protocol for adaptive transfer of BMMCs in the cockroach allergen-induced mouse model of asthma. (B) Colocalization of c-Kit (green) and ox-CaMKII (red) in the lung sections of MMVVδ mice with adoptively transferred WT and MMVVδ BMMCs. Scale bar: 100 μm (first and third row); 20 μm (second and fourth row). (C and D) Numbers of c-Kit–positive cells (C) and cells positive for both c-Kit and ox-CaMKII (D) from WT and MMVVδ mice with adoptive transfer of WT and MMVVδ BMMCs. Mean ± SEM, n = 8 high power field view (HFV) per group. (E) Representation of H&E-stained paraffin lung tissue sections from WT and MMVVδ mice adoptively transferred with WT or MMVVδ BMMCs in a CRE-induced mouse model of asthma (6 mice per group). Scale bar: 100 μm. (F and G) Systemic airway resistance (F) and compliance (G) in response to increasing concentrations of methacholine using the forced oscillation technique (FlexiVent, SCIREQ). Data represent mean ± SEM, 6 mice per group. (H and I) Bronchoalveolar lavage (BAL) total (H) and differential (I) cell counts of CRE-challenged WT and MMVVδ mice. Mean ± SEM, 7 mice per group. (J) Serum levels of cockroach allergen-specific IgE and IgG1. Mean ± SEM, 7 mice per group. (K) Levels of IL-4 (n = 7), IL-5 (n = 12), and IL-13 (n = 12) in BALs. Data represent mean ± SEM; comparisons were made using 2-tailed Student’s t test of CRE-treated MMVVδ vs. MMVVδ with adoptively transferred WT BMMCs and MMVVδ with adoptively transferred WT vs. MMVVδ BMMCs. *P < 0.05, **P < 0.01, ***P < 0.001.