CaMKII Oxidation Regulates Cockroach Allergen-Induced Mitophagy in Asthma

ABSTRACT Background Autophagy plays an important role in causing inflammatory responses initiated by environmental pollutants and respiratory tract infection. Objective We sought to investigate the role of cockroach allergen-induced excessive activation of autophagy in allergic airway inflammation and its underlying molecular mechanisms. Methods Environmental allergen-induced autophagy was investigated in the primary human bronchial epithelial cells (HBECs) and lung tissues of asthmatic mouse model and patients. The role of autophagy in asthma development was examined by using autophagy inhibitor 3-Methyladenine (3-MA) in an asthma mouse model. Further, the involvements of reactive oxygen species (ROS) and oxidized Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) signaling in regulating autophagy during asthma were examined in allergen-treated HBECs and mouse model. Results Cockroach allergen activated autophagy in HBECs and in the lung tissues from asthmatic patients and mice. Autophagy inhibitor 3-MA significantly attenuated airway hyper-responsiveness (AHR), Th2-associated lung inflammation and ROS generation. Mechanistically, we demonstrated a pathological feedforward circuit between cockroach allergen-induced ROS and autophagy that is mediated through CaMKII oxidation. Furthermore, transgenic mice with ROS-resistant CaMKII MM-VVδ showed attenuation of Th2-associated lung inflammation and autophagy. Mitochondrial ox-CaMKII inhibition induced by adenovirus carrying mitochondrial-targeted inhibitor peptide CaMKIIN suppresses cockroach allergen-induced autophagy, mitochondrial dysfunction, mitophagy, and cytokine production in HBECs. Finally, mitochondrial CaMKII inhibition suppressed the expression of one of the key ubiquitin binding autophagy receptors, optineurin (OPTN), and its recruitment to fragmented mitochondria. OPTN knockdown inhibited cockroach allergy-induced mitophagy. Conclusion Our data suggest a previously uncovered axis of allergen-ROS-ox-CaMKII-mitophagy in the development of allergic airway inflammation and asthma.