1. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria.
- Author
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Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C, Stuart LM, Leong JM, and Fitzgerald KA
- Subjects
- Animals, Carrier Proteins metabolism, Caspases, Initiator, Citrobacter rodentium immunology, Enterohemorrhagic Escherichia coli immunology, Gram-Negative Bacteria immunology, Gram-Negative Bacteria metabolism, Gram-Positive Bacteria immunology, Gram-Positive Bacteria metabolism, Mice, NLR Family, Pyrin Domain-Containing 3 Protein, Signal Transduction, Adaptor Proteins, Vesicular Transport metabolism, Caspases metabolism, Citrobacter rodentium metabolism, Enterohemorrhagic Escherichia coli metabolism, Inflammasomes metabolism, Interferons metabolism
- Abstract
Systemic infections with Gram-negative bacteria are characterized by high mortality rates due to the "sepsis syndrome," a widespread and uncontrolled inflammatory response. Though it is well recognized that the immune response during Gram-negative bacterial infection is initiated after the recognition of endotoxin by Toll-like receptor 4, the molecular mechanisms underlying the detrimental inflammatory response during Gram-negative bacteremia remain poorly defined. Here, we identify a TRIF pathway that licenses NLRP3 inflammasome activation by all Gram-negative bacteria. By engaging TRIF, Gram-negative bacteria activate caspase-11. TRIF activates caspase-11 via type I IFN signaling, an event that is both necessary and sufficient for caspase-11 induction and autoactivation. Caspase-11 subsequently synergizes with the assembled NLRP3 inflammasome to regulate caspase-1 activation and leads to caspase-1-independent cell death. These events occur specifically during infection with Gram-negative, but not Gram-positive, bacteria. The identification of TRIF as a regulator of caspase-11 underscores the importance of TLRs as master regulators of inflammasomes during Gram-negative bacterial infection., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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