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

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

Research output: Contribution to journalArticle

127 Scopus citations

Abstract

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-κB 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.

Original languageEnglish (US)
Pages (from-to)1953-1968
Number of pages16
JournalJournal of Experimental Medicine
Volume209
Issue number11
DOIs
StatePublished - Oct 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Tauseef, M., Knezevic, N., Chava, K. R., Smith, M., Sukriti, S., Gianaris, N., Obukhov, A. G., Vogel, S. M., Schraufnage, D. E., Dietrich, A., Birnbaumer, L., Malik, A. B., & Mehta, D. (2012). TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxininduced lung vascular permeability and inflammation. Journal of Experimental Medicine, 209(11), 1953-1968. https://doi.org/10.1084/jem.20111355