Irgm2 and Gate-16 put a break on caspase-11 activation.

In infections caused by gram-negative bacteria, the bacterial cell wall component lipopolysaccharide (LPS) acts as a potent pathogen-associated molecular pattern (PAMP) that triggers the innate immune system. This is accomplished by two pattern recognition receptor systems. Toll-like receptor 4 (TLR4) senses extracellular LPS and induces a broad pro-inflammatory transcriptional program and also antiviral interferons. A complementary system detects intracellular LPS. As such, upon its release into the cytoplasm, LPS can directly engage the protease caspase-4 (caspase-11 in the murine system) and thereby trigger a pro-inflammatory cell death program known as pyroptosis (Rathinam et al, 2019). This is mediated by active caspase-4 cleaving its substrate gasdermin D (GSDMD). The thereby released N-terminal fragment of GSDMD inserts into the cell membrane and forms a cytotoxic pore. As a consequence, the cell ruptures and releases its pro-inflammatory content. In addition, the GSDMD pore results in potassium efflux that can activate the NLRP3 inflammasome. NLRP3 in turn activates caspase-1, which matures pro-IL-1β and pro-IL-18, further perpetuating the inflammatory nature of this cell death. Given its unconventional mode of NLRP3 activation, this pathway has been coined the non-canonical inflammasome.

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