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Pflügers Archiv - European Journal of Physiology

, Volume 467, Issue 12, pp 2541–2554 | Cite as

Smooth muscle CaMKIIδ promotes allergen-induced airway hyperresponsiveness and inflammation

  • Amy M. Spinelli
  • Yongfeng Liu
  • Li-Yan Sun
  • José C. González-Cobos
  • Johannes Backs
  • Mohamed Trebak
  • Harold A. SingerEmail author
Molecular and cellular mechanisms of disease

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 Ca2+ signal effectors are incompletely understood. In the present study, we tested the function of ASM multifunctional protein kinase Ca2+/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.

Keywords

CaMKII Airway smooth muscle Atopic asthma Airway remodeling Airway hyperresponsiveness 

Notes

Acknowledgments

The authors greatly acknowledge the following research support: AMC’s Candice Weir Fund, NIH grant HL097111 (to MT), NIH grant HL049426 (to HAS), and Albany Medical Center fellowship and stipend support (AMS). We would also like to acknowledge receipt of generous gifts including founder mice carry floxed CaMKIIδ and CaMKIIγ alleles which were kindly provided by Dr. Johannes Backs (Heidelberg) and Dr. Eric Olson (UTSW) and the eosinophil-specific MPB antibody, provided by Dr. Jamie Lee (Mayo Clinic Scottsdale, Arizona). We also thank Xiaolan Ding, Miao Jiang, and Diane Singer for their general animal and cell culture support, Dr. Margarida Barroso for her assistance and insight into immunohistochemical and microscopy techniques, and the Singer, Trebak, and Jourd’heuil lab for the exchange of ideas and experiences on the first floor of the ME building at AMC.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Amy M. Spinelli
    • 1
    • 2
  • Yongfeng Liu
    • 1
  • Li-Yan Sun
    • 1
  • José C. González-Cobos
    • 1
    • 4
  • Johannes Backs
    • 3
  • Mohamed Trebak
    • 2
  • Harold A. Singer
    • 1
    Email author
  1. 1.Center for Cardiovascular SciencesAlbany Medical CollegeAlbanyUSA
  2. 2.Department of Cellular and Molecular PhysiologyThe Pennsylvania State University College of MedicineHersheyUSA
  3. 3.Laboratory for Cardiac Epigenetics, Department of CardiologyUniversity of Heidelberg, and German Center for Cardiovascular Research (DZHK)HeidelbergGermany
  4. 4.Barlovento Brewing CompanyManatiPuerto Rico

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