Bacterial Pore-Forming Toxins Promote the Activation of Caspases in Parallel to Necroptosis to Enhance Alarmin Release and Inflammation During Pneumonia

Sci Rep. 2018 Apr 11;8(1):5846. doi: 10.1038/s41598-018-24210-8.


Pore-forming toxins are the most common virulence factor in pathogenic bacteria. They lead to membrane permeabilization and cell death. Herein, we show that respiratory epithelial cells (REC) undergoing bacterial pore-forming toxin (PFT)-induced necroptosis simultaneously experienced caspase activation independently of RIPK3. MLKL deficient REC treated with a pan-caspase inhibitor were protected in an additive manner against PFT-induced death. Subsequently, cleaved versions of caspases-2, -4 and -10 were detected within REC undergoing necroptosis by immunoblots and monoclonal antibody staining. Caspase activation was observed in lung samples from mice and non-human primates experiencing Gram-negative and Gram-positive bacterial pneumonia, respectively. During apoptosis, caspase activation normally leads to cell shrinkage, nuclear condensation, and immunoquiescent death. In contrast, caspase activity during PFT-induced necroptosis increased the release of alarmins to the extracellular milieu. Caspase-mediated alarmin release was found sufficient to activate resting macrophages, leading to Interleukin-6 production. In a mouse model of Gram-negative pneumonia, deletion of caspases -2 and -11, the mouse orthologue of caspase-4, reduced pulmonary inflammation, immune cell infiltration and lung damage. Thus, our study describes a previously unrecognized role for caspase activation in parallel to necroptosis, and indicates that their activity plays a critical pro-inflammatory role during bacterial pneumonia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Alarmins / immunology
  • Alarmins / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Bacterial Toxins / immunology
  • Bacterial Toxins / metabolism*
  • Caspase Inhibitors / pharmacology
  • Caspases / genetics
  • Caspases / immunology
  • Caspases / metabolism*
  • Cell Membrane / ultrastructure
  • Disease Models, Animal
  • Female
  • Humans
  • Lung / cytology
  • Lung / drug effects
  • Lung / pathology
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / ultrastructure
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Necrosis / immunology
  • Papio
  • Pneumonia, Bacterial / immunology*
  • Pneumonia, Bacterial / microbiology
  • Pneumonia, Bacterial / pathology
  • Pore Forming Cytotoxic Proteins / immunology
  • Pore Forming Cytotoxic Proteins / metabolism*


  • Alarmins
  • Bacterial Toxins
  • Caspase Inhibitors
  • Pore Forming Cytotoxic Proteins
  • Caspases