Methods: Ox-CaMKII in cockroach allergens induced allergic inflammation was investigated in mouse model of asthma using MM-VVδ mice. Bone marrow-derived mast cells (BMMCs) from C57BL/6 mice and MM-VVδ mice were tested using OVA. Mast cell activation including β-hexosaminidase, IL-13 secretion, histamine release, and passive cutaneous anaphylaxis (PCA) were quantified.
Results: Compared to wild type (WT), the allergen-challenged MM-VVδ mice displayed a less airway hyper-responsiveness (AHR) and inflammation. These MM-VVδ mice exhibited reduced levels of ROS and diminished recruitment of mast cells to the lungs. OVA-activated bone marrow-derived mast cells (BMMCs) from MM-VVδ showed a significant inhibition of ROS and ox-CaMKII expression. Importantly, OVA-activated MM-VVδ BMMCs had suppressed degranulation, histamine release, leukotriene C4 (LTC4) 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.
Conclusions: 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.