H5N1 Virus Hemagglutinin Inhibition of cAMP-Dependent CFTR via TLR4-Mediated Janus Tyrosine Kinase 3 Activation Exacerbates Lung Inflammation
The host tolerance mechanisms to avian influenza virus (H5N1) infection that limit tissue injury remain unknown. Emerging evidence indicates that cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent Cl− channel, modulates airway inflammation. Janus tyrosine kinase (JAK) 3, a JAK family member that plays a central role in inflammatory responses, prominently contributes to the dysregulated innate immune response upon H5N1 attachment; therefore, this study aims to elucidate whether JAK3 activation induced by H5N1 hemagglutinin (HA) inhibits cAMP-dependent CFTR channels. We performed short-circuit current, immunohistochemistry and molecular analyses of the airway epithelium in Jak3+/+ and Jak3+/− mice. We demonstrate that H5N1 HA attachment inhibits cAMP-dependent CFTR Cl− channels via JAK3-mediated adenylyl cyclase (AC) suppression, which reduces cAMP production. This inhibition leads to increased nuclear factor-kappa B (NF-κB) signaling and inflammatory responses. H5N1 HA is detected by TLR4 expressed on respiratory epithelial cells, facilitating JAK3 activation. This activation induces the interaction between TLR4 and Gαi protein, which blocks ACs. Our findings provide novel insight into the pathogenesis of acute lung injury via the inhibition of cAMP-dependent CFTR channels, indicating that the administration of cAMP-elevating agents and targeting JAK3 may activate host tolerance to infection for the management of influenza virus-induced fatal pneumonia.
The authors would like to thank Wenliang Zhou (School of Life Science, Sun Yat-sen University, Guangzhou, China) for help with experiments. This work was supported by grants from the National Key Basic Research Program of China (973 Program; 2009CB522104), the National Natural Science Foundation of China (30900576), the China Postdoctoral Science Foundation (20100480734), the Yangcheng Scholars Research Program of Guangzhou Municipal Universities (10A024G) and the Program for Tackling Key Problems in Science and Technology of the Local Government in Guangzhou (2014), China.
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