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

Norberto Gonzalez-Juarbe, Kelley M. Bradley, Ashleigh N. Riegler, Luis F. Reyes, Terry Brissac, Sang Sang Park, Marcos I. Restrepo, Carlos J. Orihuela

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Abstract

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.

Original languageEnglish (US)
Article number5846
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Gonzalez-Juarbe, N., Bradley, K. M., Riegler, A. N., Reyes, L. F., Brissac, T., Park, S. S., Restrepo, M. I., & Orihuela, C. J. (2018). Bacterial Pore-Forming Toxins Promote the Activation of Caspases in Parallel to Necroptosis to Enhance Alarmin Release and Inflammation during Pneumonia. Scientific Reports, 8(1), [5846]. https://doi.org/10.1038/s41598-018-24210-8