Pore-forming toxin-mediated ion dysregulation leads to death receptor-independent necroptosis of lung epithelial cells during bacterial pneumonia

Norberto González-Juarbe, Kelley Margaret Bradley, Anukul Taranath Shenoy, Ryan Paul Gilley, Luis Felipe Reyes, Cecilia Anahí Hinojosa, Marcos Ignacio Restrepo, Peter Herman Dube, Molly Ann Bergman, Carlos Javier Orihuela

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

We report that pore-forming toxins (PFTs) induce respiratory epithelial cell necroptosis independently of death receptor signaling during bacterial pneumonia. Instead, necroptosis was activated as a result of ion dysregulation arising from membrane permeabilization. PFT-induced necroptosis required RIP1, RIP3 and MLKL, and could be induced in the absence or inhibition of TNFR1, TNFR2 and TLR4 signaling. We detected activated MLKL in the lungs from mice and nonhuman primates experiencing Serratia marcescens and Streptococcus pneumoniae pneumonia, respectively. We subsequently identified calcium influx and potassium efflux as the key initiating signals responsible for necroptosis; also that mitochondrial damage was not required for necroptosis activation but was exacerbated by MLKL activation. PFT-induced necroptosis in respiratory epithelial cells did not involve CamKII or reactive oxygen species. KO mice deficient in MLKL or RIP3 had increased survival and reduced pulmonary injury during S. marcescens pneumonia. Our results establish necroptosis as a major cell death pathway active during bacterial pneumonia and that necroptosis can occur without death receptor signaling.

Original languageEnglish (US)
Pages (from-to)917-928
Number of pages12
JournalCell Death and Differentiation
Volume24
Issue number5
DOIs
StatePublished - May 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    González-Juarbe, N., Bradley, K. M., Shenoy, A. T., Gilley, R. P., Reyes, L. F., Hinojosa, C. A., Restrepo, M. I., Dube, P. H., Bergman, M. A., & Orihuela, C. J. (2017). Pore-forming toxin-mediated ion dysregulation leads to death receptor-independent necroptosis of lung epithelial cells during bacterial pneumonia. Cell Death and Differentiation, 24(5), 917-928. https://doi.org/10.1038/cdd.2017.49