TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation

Mohammad Tauseef,Sukriti Sukriti,Dean E Schraufnagel,Lutz Birnbaumer,Koteswara R Chava,Alexander Dietrich,Nicholas Gianaris,Dolly Mehta,Monica Smith,Stephen M Vogel,Alexander G Obukhov,Nebojsa Knezevic,Asrar B Malik

doi:10.1083/jcb1992oia2

Abstract

TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation

Highlights

Acute lung injury (ALI) in septic patients is characterized by increased lung vascular permeability and severe lung inflammation, which typically develop in concert and lead to progressive deterioration of lung function (Diaz et al, 2010)
LPS-induced DAG generation stimulates Ca2+ entry and Ca2+ current in endothelial cell (EC) via transient receptor potential canonical 6 (TRPC6) We first addressed whether LPS generates the second messenger DAG in ECs, which in turn can activate Ca2+ entry via TRPC6.We transduced FRET-based DAG (Violin et al, 2003) and Ca2+ reporters (Kim et al, 2009) in ECs isolated from WT or Trpc6 / mouse lungs, which were stimulated with LPS
We showed that LPS induces the production of the second messenger DAG in ECs, which directly activates the cation channel TRPC6 and does so in a Toll-like receptor 4 (TLR4)-dependent manner

Summary

Introduction

Acute lung injury (ALI) in septic patients is characterized by increased lung vascular permeability and severe lung inflammation, which typically develop in concert and lead to progressive deterioration of lung function (Diaz et al, 2010). A rise in intracellular Ca2+ is an essential signal required for EC contraction that precedes endothelial barrier disruption (Mehta et al, 2003; Pocock et al, 2004; Cheng et al, 2006; Mehta and Malik, 2006; Singh et al, 2007; Kini et al, 2010; Weissmann et al, 2012) It remains unknown whether Ca2+ signaling intersects with the TLR4 signaling pathway, and contributes to LPS-induced endothelial permeability and inflammation. We tested the hypothesis that LPS ligation of TLR4 and resulting TRPC6dependent Ca2+ signaling intersect to mediate both the vascular leak and inflammatory features of ALI

Methods

Results

Conclusion