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 MMVV? knockin (MMVV?) mice. Compared with WT mice, the allergen-challenged MMVV? mice displayed less airway hyperresponsiveness (AHR) and inflammation. These MMVV? mice exhibited reduced levels of ROS and diminished recruitment of mast cells to the lungs. OVA-activated bone marrow-derived mast cells (BMMCs) from MMVV? mice showed a significant inhibition of ROS and ox-CaMKII expression. ROS generation was dependent on intracellular Ca2+ concentration in BMMCs. Importantly, OVA-activated MMVV? BMMCs had suppressed degranulation, histamine release, leukotriene C4, and IL-13 expression. Adoptive transfer of WT, but not MMVV?, BMMCs, reversed the alleviated AHR and inflammation in allergen-challenged MMVV? 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.

SUBMITTER: Qu J 

PROVIDER: S-EPMC5214090 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other