Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock

JA Hagar, DA Powell, Y Aachoui, RK Ernst, EA Miao - Science, 2013 - science.org
Science, 2013science.org
Inflammatory caspases, such as caspase-1 and-11, mediate innate immune detection of
pathogens. Caspase-11 induces pyroptosis, a form of programmed cell death, and
specifically defends against bacterial pathogens that invade the cytosol. During
endotoxemia, however, excessive caspase-11 activation causes shock. We report that
contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers
caspase-11 activation in mice. Specifically, caspase-11 responds to penta-and hexa …
Inflammatory caspases, such as caspase-1 and -11, mediate innate immune detection of pathogens. Caspase-11 induces pyroptosis, a form of programmed cell death, and specifically defends against bacterial pathogens that invade the cytosol. During endotoxemia, however, excessive caspase-11 activation causes shock. We report that contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers caspase-11 activation in mice. Specifically, caspase-11 responds to penta- and hexa-acylated lipid A, whereas tetra-acylated lipid A is not detected, providing a mechanism of evasion for cytosol-invasive Francisella. Priming the caspase-11 pathway in vivo resulted in extreme sensitivity to subsequent LPS challenge in both wild-type and Tlr4-deficient mice, whereas Casp11-deficient mice were relatively resistant. Together, our data reveal a new pathway for detecting cytoplasmic LPS.
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