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• W2893758960 endingPage "e1007338" @default.
• W2893758960 startingPage "e1007338" @default.
• W2893758960 abstract "Neutrophils are the first infiltrating cell type essential for combating pneumoseptic infections by bacterial pathogens including Klebsiella pneumoniae (KPn). Following an infection or injury, removal of apoptotic infiltrates via a highly regulated process called efferocytosis is required for restoration of homeostasis, but little is known regarding the effect of bacterial infection on this process. Here we demonstrate that KPn infection impedes the efferocytic uptake of neutrophils in-vitro and in-vivo in lungs by macrophages. This impaired efferocytosis of infected neutrophils coincides with drastic reduction in the neutrophil surface exposure of apoptosis signature phospholipid phosphatidyserine (PS); and increased activity of phospholipid transporter flippases, which maintain PS in the inner leaflet of plasma membrane. Concomitantly, pharmacological inhibition of flippase activity enhanced PS externalization and restored the efferocytosis of KPn infected neutrophils. We further show that KPn infection interferes with apoptosis activation and instead activates non-apoptotic programmed cell death via activation of necroptosis machinery in neutrophils. Accordingly, pharmacological inhibition of necroptosis by RIPK1 and RIPK3 inhibitors restored the efferocytic uptake of KPn infected neutrophils in-vitro. Importantly, treatment of KPn infected mice with necroptosis inhibitor improved the disease outcome in-vivo in preclinical mouse model of KPn pneumonia. To our knowledge, this is the first report of neutrophil efferocytosis impairment by KPn via modulation of cell death pathway, which may provide novel targets for therapeutic intervention of this infection." @default.
• W2893758960 created "2018-10-05" @default.
• W2893758960 creator A5021888023 @default.
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• W2893758960 creator A5044295250 @default.
• W2893758960 creator A5049676837 @default.
• W2893758960 date "2018-10-01" @default.
• W2893758960 modified "2023-10-15" @default.
• W2893758960 title "Klebsiella pneumoniae infection of murine neutrophils impairs their efferocytic clearance by modulating cell death machinery" @default.
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• W2893758960 doi "https://doi.org/10.1371/journal.ppat.1007338" @default.
• W2893758960 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6181436" @default.
• W2893758960 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30273394" @default.
• W2893758960 hasPublicationYear "2018" @default.
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