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
• Journal: JCI insight (JCI Insight) Vol. 2 Issue 3 Pg. e88297 (02 09 2017) ISSN: 2379-3708 [Print] United States
• PMID: 28194433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antioxidants
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Peptides
• Reactive Oxygen Species
• Ovalbumin
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Animals
• Antioxidants (administration & dosage, pharmacology)
• Aspergillus fumigatus (pathogenicity)
• Asthma (drug therapy, etiology, genetics, metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors)
• Cells, Cultured
• Disease Models, Animal
• Gene Expression Regulation (drug effects)
• Humans
• Mice
• Mice, Transgenic
• Mitochondria (drug effects, enzymology)
• NF-kappa B (genetics, metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Ovalbumin (adverse effects)
• Peptides (administration & dosage, pharmacology)
• Reactive Oxygen Species (metabolism)