Cation channel TRPC6 activation of TLR4 in endothelial cells mediates sepsis‐induced acute lung injury

Abstract

Loss of lung vascular endothelial cell (EC) barrier integrity and inflammation are main pathogenic features of acute lung injury (ALI). Activation of transient receptor potential canonical channels (TRPC) induces intracellular Ca2+ signaling, which promotes lung vascular permeability. In addition, it is known that LPS binding to TLR4 is crucial in mediating lung inflammation. However, the fundamental question whether TLR4 and Ca2+ signaling converge to induce lung vascular leakiness and inflammation is unknown. Here we show that deficiency of the TRPC6 isoform prevented TLR4‐mediated signaling in endothelial cells rendering Trpc6−/− mice resistant to endotoxin‐ and sepsis‐induced lung injury. We observed that LPS‐mediated diacylglycerol generation was responsible for inducing TRPC6 activity which in turn activated non‐muscle myosin light chain kinase (MYLK) in endothelial cells. Activated MYLK promoted MyD88 and IRAK4 interaction leading to activation of TLR4 signaling. Our findings therefore identified TRPC6 as an essential switch that “turns on” LPS‐induced increase in lung vascular hyper‐permeability and lung inflammation. Thus, strategies aimed at blocking the instigating TRPC6 activity may hold the key to preventing acute lung injury.