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 3

Allergen-induced eosinophilia is attenuated in Mt-CaMKIIN mice.

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Allergen-induced eosinophilia is attenuated in Mt-CaMKIIN mice. (A and B...
(A and B) Total cell counts in bronchoalveolar lavage fluid (BALF) from mice exposed to (A) A. fumigatus or (B) OVA (A. fumigatus: n = 7 WT control; 5 Mt-CaMKIIN control; 10 WT A. fumigatus; and 8 Mt-CaMKIIN A. fumigatus–treated mice — OVA: n = 14 WT or Mt-CaMKIIN control; 13 WT OVA; and 7 Mt-CaMKIIN OVA-treated mice). Triangles: WT mice; circles: Mt-CaMKIIN mice. (C and D) Eosinophils in BALF from (C) A. fumigatus– or (D) OVA-exposed mice (A. fumigatus: n = 7 WT control; 5 Mt-CaMKIIN control; and 6–8 A. fumigatus–treated mice; OVA: n = 6–7 control; 5–6 OVA-treated mice). (E and F) Representative H&E staining and quantification of eosinophil infiltration in (E) A. fumigatus– and (F) OVA-challenged mice (original magnification, ×40, Scale bar: 50 μm). The number of eosinophils per 10 μm2 area (original magnification, ×100, Scale bar: 1 mm) in 4–6 sections per mouse was quantified. (A. fumigatus: n = 4 WT control; 4 Mt-CaMKIIN control; and 4–5 A. fumigatus–treated mice; OVA: n = 6 WT control; 3 Mt-CaMKIIN control; 8 WT-OVA; and 5 Mt-CaMKIIN OVA–treated mice). (G and H) Representative PAS staining and quantification from (G) A. fumigatus– or (H) OVA-exposed mice (original magnification, ×20, scale bar: 25 μm). Data were quantified in 4–6 sections per mouse (A. fumigatus: n = 4 control and 5 A. fumigatus–treated mice; OVA: n = 6 control and 4–5 OVA-treated mice). *P < 0.05 vs. control; #P < 0.05 vs WT mice with A. fumigatus or OVA exposure.