Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma
Sara C. Sebag, Olha M. Koval, John D. Paschke, Christopher J. Winters, Omar A. Jaffer, Ryszard Dworski, Fayyaz S. Sutterwala, Mark E. Anderson, Isabella M. Grumbach
Sara C. Sebag, Olha M. Koval, John D. Paschke, Christopher J. Winters, Omar A. Jaffer, Ryszard Dworski, Fayyaz S. Sutterwala, Mark E. Anderson, Isabella M. Grumbach
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Research Article Inflammation Pulmonology

Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

Abstract

Excessive ROS promote allergic asthma, a condition characterized by airway inflammation, eosinophilic inflammation, and increased airway hyperreactivity (AHR). The mechanisms by which airway ROS are increased and the relationship between increased airway ROS and disease phenotypes are incompletely defined. Mitochondria are an important source of cellular ROS production, and our group discovered that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is present in mitochondria and activated by oxidation. Furthermore, mitochondrial-targeted antioxidant therapy reduced the severity of allergic asthma in a mouse model. Based on these findings, we developed a mouse model of CaMKII inhibition targeted to mitochondria in airway epithelium. We challenged these mice with OVA or Aspergillus fumigatus. Mitochondrial CaMKII inhibition abrogated AHR, inflammation, and eosinophilia following OVA and A. fumigatus challenge. Mitochondrial ROS were decreased after agonist stimulation in the presence of mitochondrial CaMKII inhibition. This correlated with blunted induction of NF-κB, the NLRP3 inflammasome, and eosinophilia in transgenic mice. These findings demonstrate a pivotal role for mitochondrial CaMKII in airway epithelium in mitochondrial ROS generation, eosinophilic inflammation, and AHR, providing insights into how mitochondrial ROS mediate features of allergic asthma.

Authors

Sara C. Sebag, Olha M. Koval, John D. Paschke, Christopher J. Winters, Omar A. Jaffer, Ryszard Dworski, Fayyaz S. Sutterwala, Mark E. Anderson, Isabella M. Grumbach

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Figure 5

Mt-CaMKII inhibition in airway epithelium abrogates allergen-induced inflammatory cytokine expression in vivo.

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Mt-CaMKII inhibition in airway epithelium abrogates allergen-induced inf...
(A and B) qRT-PCR for eotaxin in lungs from (A) A. fumigatus– or (B) OVA-challenged WT or Mt-CaMKIIN mice (n = 5–7 controls and 5 WT A. fumigatus and 10 Mt-CaMKIIN A. fumigatus–treated mice or 3 controls and 4–5 OVA-treated mice). (C and D) qRT-PCR for IL-4 in lungs of (C) A. fumigatus– or (D) OVA-challenged WT or Mt-CaMKIIN mice (n = 5–6 controls and 5 WT A. fumigatus and 9 Mt-CaMKIIN A. fumigatus–treated mice or 7–8 controls and 9–10 OVA-treated mice). (E) ELISA for IL-4 protein in lungs from OVA-challenged WT or Mt-CaMKIIN mice (n = 3 WT control; 8 Mt-CaMKIIN control; 4 WT-OVA; and 7 Mt-CaMKIIN OVA-treated mice). (F) qRT-PCR for IL-5 in lungs from OVA-challenged WT or Mt-CaMKIIN mice (n = 7–8 controls and 9–10 OVA-treated mice). (G) ELISA for IL-5 in lungs from mice after OVA challenge (n = 6 controls and 10 OVA-treated mice). (H and I) ELISA for IL-13 protein in lungs of (H) A. fumigatus– or (I) OVA-challenged WT or Mt-CaMKIIN mice (n = 4 controls and 8 A. fumigatus–treated mice or 4–5 controls and 5–7 OVA-treated mice). ANOVA was used with Tukey post-hoc test. *P < 0.05 vs. control or saline; #P < 0.05 vs. WT mice with A. fumigatus or OVA exposure. Triangles: WT mice; circles: Mt-CaMKIIN mice.