posted on 2013-12-05, 00:00authored byMohammad Tauseef, Nebojsa Knezevic, Koteswara R. Chava, Monica Smith, Sukriti Sukriti, Nicholas Gianaris, Alexander G. Obukhov, Stephen M. Vogel, Dean E. Schraufnagel, Alexander Dietrich, Lutz Birnbaumer, Asrar B. Malik, Dolly Mehta
Lung vascular endothelial barrier disruption and the accompanying inflammation are primary
pathogenic features of acute lung injury (ALI); however, the basis for the development
of both remains unclear. Studies have shown that activation of transient receptor
potential canonical (TRPC) channels induces Ca2+ entry, which is essential for increased
endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection
with TRPC6-dependent Ca2+ signaling in endothelial cells (ECs) in mediating lung
vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS)
induces Ca2+ entry in ECs in a TLR4-dependent manner. Moreover, deletion of TRPC6
renders mice resistant to endotoxin-induced barrier dysfunction and inflammation, and
protects against sepsis-induced lethality. TRPC6 induces Ca2+ entry in ECs, which is secondary
to the generation of diacylglycerol (DAG) induced by LPS. Ca2+ entry mediated by
TRPC6, in turn, activates the nonmuscle myosin light chain kinase (MYLK), which not only
increases lung vascular permeability but also serves as a scaffold to promote the interaction
of myeloid differentiation factor 88 and IL-1R–associated kinase 4, which are required for
NF-B activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca2+
entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both
lung vascular barrier disruption and inflammation induced by endotoxin.
Funding
National Institutes of Health grants HL71794
(D. Mehta), HL84153 (D. Mehta) and PO1-HL60678 (D. Mehta and A.B. Malik),
Tauseef M, Knezevic N, Chava KR, Smith M, Sukriti S, Gianaris N, Obukhov AG, Vogel SM, Schraufnagel DE, Dietrich A, Birnbaumer L, Malik AB, Mehta D. TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation. Journal of Experimental Medicine . 2012 Oct 22;209(11):1953-68. doi: 10.1084/jem.20111355.