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Reduction of streptolysin O (SLO) pore-forming activity enhances inflammasome activation.
- Source :
-
Toxins [Toxins (Basel)] 2013 Jun 06; Vol. 5 (6), pp. 1105-18. Date of Electronic Publication: 2013 Jun 06. - Publication Year :
- 2013
-
Abstract
- Pore-forming toxins are utilized by bacterial and mammalian cells to exert pathogenic effects and induce cell lysis. In addition to rapid plasma membrane repair, macrophages respond to pore-forming toxins through activation of the NLRP3 inflammasome, leading to IL-1β secretion and pyroptosis. The structural determinants of pore-forming toxins required for NLRP3 activation remain unknown. Here, we demonstrate using streptolysin O (SLO) that pore-formation controls IL-1β secretion and direct toxicity. An SLO mutant incapable of pore-formation did not promote direct killing, pyroptosis or IL-1β production. This indicated that pore formation is necessary for inflammasome activation. However, a partially active mutant (SLO N402C) that was less toxic to macrophages than wild-type SLO, even at concentrations that directly lysed an equivalent number of red blood cells, enhanced IL-1β production but did not alter pyroptosis. This suggests that direct lysis may attenuate immune responses by preventing macrophages from successfully repairing their plasma membrane and elaborating more robust cytokine production. We suggest that mutagenesis of pore-forming toxins represents a strategy to enhance adjuvant activity.
- Subjects :
- Animals
Bacterial Proteins genetics
Bacterial Proteins pharmacology
CHO Cells
Caspase 1 deficiency
Caspase 1 genetics
Cell Death
Cells, Cultured
Cricetinae
Cricetulus
Interleukin-1beta metabolism
Lipopolysaccharides
Macrophages metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutagenesis
Inflammasomes metabolism
Macrophages drug effects
Streptolysins genetics
Streptolysins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2072-6651
- Volume :
- 5
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Toxins
- Publication Type :
- Academic Journal
- Accession number :
- 23744055
- Full Text :
- https://doi.org/10.3390/toxins5061105