A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation

István Czikora, Abdel Alli, Hui Fang Bao, David Kaftan, Supriya Sridhar, Hans Jürgen Apell, Boris Gorshkov, Richard White, Astrid Zimmermann, Albrecht Wendel, Meike Pauly-Evers, Jürg Hamacher, Irène Garcia-Gabay, Bernhard Fischer, Alexander Verin, Zsolt Bagi, Jean Francois Pittet, Waheed Shabbir, Rosa Lemmens-Gruber, Trinad ChakrabortyAhmed Lazrak, Michael A. Matthay, Douglas C. Eaton, Rudolf Lucas

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Rationale: Alveolar liquid clearance is regulated by Na+ uptake through the apically expressed epithelial sodium channel (ENaC) and basolaterally localized Na+-K+-ATPase in type II alveolar epithelial cells. Dysfunction of these Na+ transporters during pulmonary inflammation can contribute to pulmonary edema. Objectives: In this study, we sought to determine the precise mechanism by which the TIP peptide, mimicking the lectin-like domain of tumor necrosis factor (TNF), stimulates Na+ uptake in a homologous cell system in the presence or absence of the bacterial toxin pneumolysin (PLY). Methods: We used a combined biochemical, electrophysiological, and molecular biological in vitro approach and assessed the physiological relevance of the lectin-like domain of TNF in alveolar liquid clearance in vivo by generating triple-mutant TNF knock-in mice that express a mutant TNF with deficient Na+ uptake stimulatory activity. Measurements and Main Results: TIP peptide directly activates ENaC, but not the Na+-K+-ATPase, upon binding to the carboxyterminal domain of the α subunit of the channel. In the presence of PLY, a mediator of pneumococcal-induced pulmonary edema, this binding stabilizes the ENaC-PIP2-MARCKS complex, which is necessary for the open probability conformation of the channel and preserves ENaC-α protein expression, by means of blunting the protein kinase C-α pathway. Triple-mutant TNF knock-in mice are more prone than wild-type mice to develop edema with low-dose intratracheal PLY, correlating with reduced pulmonary ENaC-α subunit expression. Conclusions: These results demonstrate a novel TNF-mediated mechanism of direct ENaC activation and indicate a physiological role for the lectin-like domain of TNF in the resolution of alveolar edema during inflammation.

Original languageEnglish (US)
Pages (from-to)522-532
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume190
Issue number5
DOIs
StatePublished - Sep 1 2014

Keywords

  • Epithelial sodium channel
  • Pneumonia
  • Protein kinase C-α
  • Pulmonary edema
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Czikora, I., Alli, A., Bao, H. F., Kaftan, D., Sridhar, S., Apell, H. J., Gorshkov, B., White, R., Zimmermann, A., Wendel, A., Pauly-Evers, M., Hamacher, J., Garcia-Gabay, I., Fischer, B., Verin, A., Bagi, Z., Pittet, J. F., Shabbir, W., Lemmens-Gruber, R., ... Lucas, R. (2014). A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation. American Journal of Respiratory and Critical Care Medicine, 190(5), 522-532. https://doi.org/10.1164/rccm.201405-0833OC