Figure 2. Activation of the non-canonical NLRP3 inflammasome.
Activation of the non-canonical NLRP3 inflammasome involves interferon-inducible caspase-11. Induction of IFN-β expression by Gram-negative bacteria relies on activation of endosomal/phagosomal TLR4 and the signaling pathway downstream of the adaptor TRIF. Secreted IFN-β then activates IFNAR, notably in an autocrine manner, which promotes expression of pro-caspase-11 and additional IFN-inducible proteins such as GBPs. Caspase-11 is activated by direct binding of intracellular LPS, released from the phagosomes, to the CARD domain of caspase-11. GBPs are recruited to the phagosome and participate in phagosomal lysis and release of LPS in the cytoplasm. Active caspase-11 directly cleaves Gasdermin D to induce pyroptosis, and also leads to activation of the NLRP3 inflammasome via uncharacterized mechanisms.