TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria

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...

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Published in:Cell Vol. 150; no. 3; p. 606
Main Authors: Rathinam, Vijay A K, Vanaja, Sivapriya Kailasan, Waggoner, Lisa, Sokolovska, Anna, Becker, Christine, Stuart, Lynda M, Leong, John M, Fitzgerald, Katherine A
Format: Journal Article
Language:English
Published: United States 03.08.2012
Subjects:
Adaptor Proteins, Vesicular Transport - metabolism
Animals
Carrier Proteins - metabolism
Caspases - metabolism
Citrobacter rodentium - immunology
Citrobacter rodentium - metabolism
Enterohemorrhagic Escherichia coli - immunology
Enterohemorrhagic Escherichia coli - metabolism
Gram-Negative Bacteria - immunology
Gram-Negative Bacteria - metabolism
Gram-Positive Bacteria - immunology
Gram-Positive Bacteria - metabolism
Inflammasomes - metabolism
Interferons - metabolism
Mice
NLR Family, Pyrin Domain-Containing 3 Protein
Signal Transduction
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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Summary: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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2012.07.007