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Toxins 2013, 5(6), 1105-1118; doi:10.3390/toxins5061105

Reduction of Streptolysin O (SLO) Pore-Forming Activity Enhances Inflammasome Activation

1 Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15260, USA 2 Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA 3 Howard Hughes Medical Institute and Rheumatology Division, Department of Medicine, Washington University, St. Louis, MO 63110, USA
* Author to whom correspondence should be addressed.
Received: 1 March 2013 / Revised: 29 May 2013 / Accepted: 3 June 2013 / Published: 6 June 2013
(This article belongs to the Special Issue Pore-Forming Toxins)
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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.
Keywords: NLRP3; inflammasome; Caspase-1; plasma membrane repair; streptolysin O NLRP3; inflammasome; Caspase-1; plasma membrane repair; streptolysin O
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keyel, P.A.; Roth, R.; Yokoyama, W.M.; Heuser, J.E.; Salter, R.D. Reduction of Streptolysin O (SLO) Pore-Forming Activity Enhances Inflammasome Activation. Toxins 2013, 5, 1105-1118.

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