Transient receptor potential vanilloid 4 is a critical mediator in LPS mediated inflammation by mediating calcineurin/NFATc3 signaling

• Published in: Biochemical and biophysical research communications 2019-06, Vol.513 (4), p.1005-1012
• Main Authors: Li, Min, Fang, Xiang-Zhi, Zheng, Yong-Feng, Xie, Yun-Bin, Ma, Xiao-Dong, Liu, Xiao-Tian, Xia, Yan, Shao, Dong-Hua
• Format: Article
• Language: English
• Subjects: Calcineurin; Inflammation; Lung injury; TRPV4
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.04.020

Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is thought to be an essential component of inflammatory response. However, its role and mechanism in regulating acute lung injury (ALI) and macrophages activation are not well characterized. In our study, we observe that blockade of TRPV4 using GSK2193874 or HC-067047 greatly improve the pneumonedema, the lung pathologic changes, the up-regulation of proinflammatory cytokines and the neutrophil infiltration in LPS-induced lung injury. In vitro, knockdown of TRPV4 in macrophages reduces the levels of pro-inflammatory cytokines, ROS production, Ca2+ concentration in cytoplasma and the activation of calcineurin/NFATc3 signaling. Importantly, change of extracellular Ca2+ in culture medium prevents LPS-induced NFATc3 nuclear translocation, up-regulation of proinflammatory cytokines and ROS production in macrophages. Inhibition of calcineurin with cyclosporine A, FK506 down-regulates the levels of NFATc3 nuclear translocation and proinflammatory cytokines expression. Our results demonstrate that TRPV4-dependent Ca2+ influx contributes to LPS-induced macrophage activation by calcineurin-NFATc3 pathway. •Blockade of TRPV4 attenuated LPS-induced lung injury and lung inflammation.•Knockdown of TRPV4 decreased LPS- induced up-regulation of pro-inflammatory cytokines and ROS production in macrophages.•TRPV4-Ca2+-calcineurin-NFATc3 signaling is required for LPS-induced macrophage activation and inflammation.