title: 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.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Qu
authors.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Danh C
authors.initials: DC
authors.lastname: Do
authors.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|Institute of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China; Key Laboratory of Neonatal Diseases, Ministry of Health, Shanghai, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luczak
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Mitzner
authors.affiliation: Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Peisong
authors.initials: P
authors.lastname: Gao
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology; D001596:Benzylamines / Q000008:administration & dosage / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D006969:Hypersensitivity, Immediate / Q000378:metabolism; D007249:Inflammation; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012130:Respiratory Hypersensitivity / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides