TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells

• Published in: Nature communications Vol. 8; no. 1; pp. 1059 - 13
• Main Authors: Alpizar, Yeranddy A., Boonen, Brett, Sanchez, Alicia, Jung, Carole, López-Requena, Alejandro, Naert, Robbe, Steelant, Brecht, Luyts, Katrien, Plata, Cristina, De Vooght, Vanessa, Vanoirbeek, Jeroen A. J., Meseguer, Victor M., Voets, Thomas, Alvarez, Julio L., Hellings, Peter W., Hoet, Peter H. M., Nemery, Benoit, Valverde, Miguel A., Talavera, Karel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.10.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/2499; 631/443/1784; 631/80/86/2372; Bacteria; Calcium (intracellular); Cell activation; Cell walls; Cilia beat frequency; Epithelial cells; Epithelium; Genètica; Genètica bacteriana; Gram-negative bacteria; Humanities and Social Sciences; Immune clearance; Immune response; Immune system; Inflammation; Leukocyte migration; Leukocytes; Leukocytes (polymorphonuclear); Lipopolysaccharides; Mice; multidisciplinary; Nitric oxide; Polisacàrids; Respiratory tract; Rodents; Science; Science (multidisciplinary); TLR4 protein; Toll-like receptors; Transient receptor potential proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01201-3

Lipopolysaccharides (LPS), the major components of the wall of gram-negative bacteria, trigger powerful defensive responses in the airways via mechanisms thought to rely solely on the Toll-like receptor 4 (TLR4) immune pathway. Here we show that airway epithelial cells display an increase in intracellular Ca 2+ concentration within seconds of LPS application. This response occurs in a TLR4-independent manner, via activation of the transient receptor potential vanilloid 4 cation channel (TRPV4). We found that TRPV4 mediates immediate LPS-induced increases in ciliary beat frequency and the production of bactericidal nitric oxide. Upon LPS challenge TRPV4-deficient mice display exacerbated ventilatory changes and recruitment of polymorphonuclear leukocytes into the airways. We conclude that LPS-induced activation of TRPV4 triggers signaling mechanisms that operate faster and independently from the canonical TLR4 immune pathway, leading to immediate protective responses such as direct antimicrobial action, increase in airway clearance, and the regulation of the inflammatory innate immune reaction. LPS is a major component of gram-negative bacterial cell walls, and triggers immune responses in airway epithelium by activating TLR4. Here the authors show that LPS also activates TRPV4, thereby inducing fast defense responses such as nitric oxide production and increased ciliary beating in mice.