TRIF Licenses Caspase-11-Dependent NLRP3 Inflammasome Activation by Gram-Negative Bacteria

• Published in: Cell Vol. 150; no. 3; pp. 606 - 619
• 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 Elsevier Inc 03-08-2012
• Subjects: Adaptor Proteins, Vesicular Transport - metabolism; Animals; Bacteremia; bacterial infections; Carrier Proteins - metabolism; Caspase-1; Caspase-11; Caspases - metabolism; Cell death; Citrobacter rodentium - immunology; Citrobacter rodentium - metabolism; Disseminated infection; Endotoxins; Enterohemorrhagic Escherichia coli - immunology; Enterohemorrhagic Escherichia coli - metabolism; Gram-negative bacteria; Gram-Negative Bacteria - immunology; Gram-Negative Bacteria - metabolism; Gram-positive bacteria; Gram-Positive Bacteria - immunology; Gram-Positive Bacteria - metabolism; Immune response; infection; Inflammasomes - metabolism; Inflammation; Interferon; Interferons - metabolism; Mice; Molecular modelling; Mortality; NLR Family, Pyrin Domain-Containing 3 Protein; Sepsis; Signal Transduction; Synergism; TLR4 protein; Toll-like receptor 4; Toll-like receptors
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.07.007

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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► TRIF is essential for NLRP3 inflammasome activation by EHEC and C. rodentium ► TRIF signaling via type I interferon couples caspase-11 induction and autoactivation ► The TRIF-IFN-caspase-11 axis licenses NLRP3 inflammasome activation ► Caspase-11 activation licenses NLRP3 activation by Gram-negative, but not -positive, bacteria
TRIF is as an integral component of NLRP3 inflammasome activation during Gram-negative bacterial infection, highlighting the central role of TLRs as master regulators of the NLRP3 inflammasome and providing new targets for therapeutic intervention in septic shock.