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

ABSTRACT: 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.

SUBMITTER: Hagar JA

PROVIDER: S-EPMC3931427 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

Hagar Jon A JA Powell Daniel A DA Aachoui Youssef Y Ernst Robert K RK Miao Edward A EA

Science (New York, N.Y.) 20130901 6151

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-a ...[more]

PMID: 24031018

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