RGD Reference Report - Pore-forming toxin-mediated ion dysregulation leads to death receptor-independent necroptosis of lung epithelial cells during bacterial pneumonia. - Rat Genome Database

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

Authors: González-Juarbe, Norberto  Bradley, Kelley Margaret  Shenoy, Anukul Taranath  Gilley, Ryan Paul  Reyes, Luis Felipe  Hinojosa, Cecilia Anahí  Restrepo, Marcos Ignacio  Dube, Peter Herman  Bergman, Molly Ann  Orihuela, Carlos Javier 
Citation: González-Juarbe N, etal., Cell Death Differ. 2017 May;24(5):917-928. doi: 10.1038/cdd.2017.49. Epub 2017 Apr 7.
RGD ID: 127229944
Pubmed: PMID:28387756   (View Abstract at PubMed)
PMCID: PMC5423117   (View Article at PubMed Central)
DOI: DOI:10.1038/cdd.2017.49   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
bacterial pneumonia amelioratesISORipk3 (Mus musculus)127229944; 127229944 RGD 
bacterial pneumonia amelioratesIMP 127229944 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ripk3  (receptor-interacting serine-threonine kinase 3)

Genes (Mus musculus)
Ripk3  (receptor-interacting serine-threonine kinase 3)

Genes (Homo sapiens)
RIPK3  (receptor interacting serine/threonine kinase 3)


Additional Information