title: Smooth muscle CaMKIIδ promotes allergen-induced airway hyperresponsiveness and inflammation.
abstract: Airway smooth muscle (ASM) is a key target cell in allergen-induced asthma known to contribute to airway hyperresponsiveness (AHR) and chronic airway remodeling. Changes in ASM calcium homeostasis have been shown to contribute to AHR although the mechanisms and Ca(2+) signal effectors are incompletely understood. In the present study, we tested the function of ASM multifunctional protein kinase Ca(2+)/calmodulin-dependent kinase II (CaMKII) isoforms CaMKIIδ and CaMKIIγ in allergen-induced AHR and airway remodeling in vivo. Using a murine model of atopic asthma, we demonstrate that CaMKIIδ protein is upregulated in ASM derived from ovalbumin (OVA)-treated animals compared to controls. A genetic approach to conditionally knock out smooth muscle CaMKIIδ and CaMKIIγ in separate Cre-loxp systems was validated, and using this loss-of-function approach, the function of these CaMKII isoforms was tested in ovalbumin (OVA)-induced airway remodeling and AHR. OVA treatment in control mice had no effect on ASM remodeling in this model of AHR, and CaMKIIδ knockouts had no independent effects on ASM content. However, at 1 day post-final OVA challenge, OVA-induced AHR was eliminated in the CaMKIIδ knockouts. OVA-induced peribronchial inflammation and bronchoalveolar lavage fluid (BALF) levels of the Th2 cytokine IL-13 were significantly decreased in the CaMKIIδ knockouts. Unexpectedly, we found increased peribronchial eosinophils in the smooth muscle CaMKIIδ knockouts compared to control animals at 1 day post-final challenge, suggesting that lack of ASM CaMKIIδ delays the progression of AHR rather than inhibiting it. Indeed, when AHR was determined at 7 days post-final OVA challenge, CaMKIIδ knockouts showed robust AHR while AHR was fully resolved in OVA-challenged control mice. These in vivo studies demonstrate a role for smooth muscle CaMKIIδ in promoting airway inflammation and AHR and suggest a complex signaling role for CaMKIIδ in regulating ASM function. These studies confirm the diverse roles of ASM cells as immune effectors that control AHR and call for further studies into CaMKIIδ-mediated signaling in ASM cells during disease.
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, USA. aspinelli@hmc.psu.edu.|Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA. aspinelli@hmc.psu.edu.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Spinelli
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, USA.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, USA.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Sun
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, USA. gonzaj2@gmail.com.|Barlovento Brewing Company, Manati, Puerto Rico. gonzaj2@gmail.com.
authors.forename: José C
authors.initials: JC
authors.lastname: González-Cobos
authors.affiliation: Laboratory for Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and German Center for Cardiovascular Research (DZHK), Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Trebak
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, USA. Singerh@mail.amc.edu.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Singer
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D010047:Ovalbumin / Q000633:toxicity
chemical_list: D018793:Interleukin-13; D007527:Isoenzymes; D010047:Ovalbumin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Airway hyperresponsiveness; Airway remodeling; Airway smooth muscle; Atopic asthma; CaMKII