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

Cell. 2012 Aug 3;150(3):606-19. doi: 10.1016/j.cell.2012.07.007. Epub 2012 Jul 19.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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

Substances

  • Adaptor Proteins, Vesicular Transport
  • Carrier Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • TICAM-1 protein, mouse
  • Interferons
  • Casp4 protein, mouse
  • Caspases