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 8

CaMKII inhibitor suppresses OVA-induced mast cell activation and PCA in vivo.

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CaMKII inhibitor suppresses OVA-induced mast cell activation and PCA in ...
BMMCs or human mast cells, HMC-1 cells, were sensitized with 1 μg/ml anti-OVA IgE (E-C1) in the presence or absence of different doses of KN-93 (1–20 μM) for 16 hours and then stimulated with PBS or 10 μg/ml OVA for 30 minutes. (A–D) Mast cell activation was assessed by measuring β-hexosaminidase (n = 3) in BMMCs (A) and HMC-1 cells (C) and IL-13 levels (n = 6) in BMMCs (B) and HMC-1 cells (D). (E) Representative images of Evans blue–stained extravasation into skin. Mice were injected intradermally with E-C1 with or without KN-93. After 24 hours, OVA was administered i.v. together with Evans blue dye for 30 minutes, followed by the quantification of the extravasation of Evans blue leakage into the skin. Data represent mean ± SEM, 3 mice per group. Comparisons were made using 2-tailed Student’s t test between OVA-treated mast cells vs. mast cells pretreated with different dosages of KN-93 and then challenged with OVA (A–D) or mice pretreated with or without KN-93 and then challenged with OVA (E). *P < 0.05, **P < 0.01.