Mechanical breathing motions have a fundamental function in lung development and disease, but little is known about how they contribute to host innate immunity. Here we use a human lung alveolus chip that experiences cyclic breathing-like deformations to investigate whether physical forces influence innate immune responses to viral infection. Influenza H3N2 infection of mechanically active chips induces a cascade of host responses including increased lung permeability, apoptosis, cell regeneration, cytokines production, and recruitment of circulating immune cells. Comparison with static chips reveals that breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells, which are mediated in part through activation of the mechanosensitive ion channel TRPV4 and signaling via receptor for advanced glycation end products (RAGE). RAGE inhibitors suppress cytokines induction, while TRPV4 inhibition attenuates both inflammation and viral burden, in infected chips with breathing motions. Therefore, TRPV4 and RAGE may serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation. Mechanical forces in lungs facilitate breathing motions. Here the authors use a microfluidic human lung alveolus chip to study influenza infection and find that mechanical forces from active chips also induce innate inflammatory responses via, at least partially, signaling from TRPV4 and RAGE, thereby implicating them as potential therapeutic targets for lung inflammation.
【저자키워드】 viral infection, Innate immunity, Antimicrobial responses, tissue engineering, 【초록키워드】 Apoptosis, Inflammation, pandemic, innate immune response, Influenza, RAGE, lung, cytokine, host response, virus, viral replication, endothelial cells, human lung, Patient, immune cells, target, receptor, recruitment, inhibitor, disease, epithelial, Protective, Signaling, Inflammatory response, Lung inflammation, host innate immunity, TRPV4, Activation, influenza infection, life-threatening, therapeutic intervention, circulating, viral burden, cascade, deformation, potential therapeutic target, physical, Cell, facilitate, contribute, induce, suppress, reveal, activating, attenuate, H3N2 infection, Mechanical, 【제목키워드】 innate immune response, human lung, Mechanical,