| First Author | Tauseef M | Year | 2012 |
| Journal | J Exp Med | Volume | 209 |
| Issue | 11 | Pages | 1953-68 |
| PubMed ID | 23045603 | Mgi Jnum | J:190915 |
| Mgi Id | MGI:5450755 | Doi | 10.1084/jem.20111355 |
| Citation | Tauseef M, et al. (2012) TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation. J Exp Med 209(11):1953-68 |
| abstractText | 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 Ca(2+) entry, which is essential for increased endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection with TRPC6-dependent Ca(2+) signaling in endothelial cells (ECs) in mediating lung vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS) induces Ca(2+) 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 Ca(2+) entry in ECs, which is secondary to the generation of diacylglycerol (DAG) induced by LPS. Ca(2+) 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-kappaB activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca(2+) entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both lung vascular barrier disruption and inflammation induced by endotoxin. |
