Toll-like receptor 4 (TLR4) has a fundamental role in the response to Gram-negative bacteria. In Cell, Fitzgerald and colleagues identify a previously unknown pathway that contributes to the response to Gram-negative bacteria. Endosomal recognition of bacteria by TLR4 is mediated by the adaptor TRIF, and certain bacteria also trigger the proinflammatory cytokines IL-1 and IL-18 via activation of the NLRP3 inflammasome. The authors find that TRIF is crucial for the response to NLRP3 triggering by Gram-negative bacteria but not by other bacteria or NLRP3 agonists. TRIF engagement typically results in the copious production of type I interferons (IFN-α and IFN-β), and these cytokines act in a feedback loop via the cognate receptor IFNAR to produce caspase-11. Although caspase-11 is unable to process and mature the key inflammasome enzyme caspase-1, it is critical for 'licensing' NLRP3 activity. This TRIF–IFNAR–caspase-11 pathway may therefore be important in the uncontrolled inflammatory amplification seen in sepsis induced by Gram-negative bacteria.

Cell 150, 606–619 (2012)