title: TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria.
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.
authors: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors: Vijay A K
authors: VA
authors: Rathinam
authors: Sivapriya Kailasan
authors: SK
authors: Vanaja
authors: Lisa
authors: L
authors: Waggoner
authors: Anna
authors: A
authors: Sokolovska
authors: Christine
authors: C
authors: Becker
authors: Lynda M
authors: LM
authors: Stuart
authors: John M
authors: JM
authors: Leong
authors: Katherine A
authors: KA
authors: Fitzgerald
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator; D044082:Citrobacter rodentium / Q000276:immunology / Q000378:metabolism*; D054324:Enterohemorrhagic Escherichia coli / Q000276:immunology / Q000378:metabolism*; D006090:Gram-Negative Bacteria / Q000276:immunology / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000276:immunology / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism*; D007372:Interferons / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D020169:Caspases; D053471:Caspases, Initiator; D058847:Inflammasomes; D007372:Interferons; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C476286:Ticam1 protein, mouse; C101136:Casp4 protein, mouse