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

By J. Hagar, D. Powell, Y. Aachoui, R. Ernst, Edward A. Miao. Science, 2013

1,196 citations recorded by the source corpus.

Move Over, TLR4 The innate immune system senses bacterial lipopolysaccharide (LPS) through Toll-like receptor 4 (TLR4) (see the Perspective by Kagan). However, Kayagaki et al. (p 1246, published online 25 July) and Hagar et al. (p. 1250) report that the hexa-acyl lipid A component of LPS from Gramnegative bacteria is able to access the cytoplasm and activate caspase-11 to signal immune responses independently of TLR4. Mice that lack caspase-11 are resistant to LPS-induced lethality, even in the presence of TLR4. Cytoplasmic lipopolysaccharide from Gram-negative bacteria can activate the innate immune system directly. [Also see Perspective by Kagan] 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.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1c80c3b9634162d2f42910756e0358231c972994

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In Epidemiology

1. G. Núñez
2. S. Gordon
3. M. Lamkanfi
4. Min Huang
5. V. Dixit
6. E. Latz
7. T. Kanneganti
8. Jingqian Su

In Molecular Biology

1. T. Kanneganti
2. M. Lamkanfi
3. S. Man
4. Edward A. Miao
5. V. Dixit
6. G. Núñez
7. R. Malireddi
8. S. Kesavardhana

Citations in the corpus

• Inflammasome - activated gasdermin D causes pyroptosis by forming membrane pores (2016, background): “To confirm lipid binding by GSDMD-NT, we measured wild-type and 4A-mutant GSDMD-NT binding and disruption of PE–PC liposomes containing no added lipid or PtdIns(4)P, PtdIns(4,5)P2, PS or PA (Fig.”
• Regulation of inflammasome activation (2015, background): “Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock.”
• Caspases in cell death, inflammation and disease (2019, background): “In this pathway, internalized lipopolysaccharide (LPS) from Gram-negative bacteria interacts with the CARD domain and activates human caspases 4 and 5 and murine caspase-11 (Baker et al., 2015; Hagar et al., 2013; Kayagaki et al., 2013; Schmid-Burgk et al., 2015; Shi et al., 2014).”
• Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation (2016, positive): “Heat killed bacteria (Sander et al., 2011) and bacterial lysates (Hagar et al., 2013) were prepared as described previously.”
• GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death (2016, positive): “In contrast, the bacterial cell wall component lipopolysaccharide (LPS), one of the strongest immune-system activators, leads to the assembly of “non-canonical” inflammasomes through activation of caspase-4, caspase-5 or caspase-11 (Kayagaki et al , 2011, 2013; Hagar et al , 2013; Shi et al , 2014).”
• NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. (2018, background): “Accordingly, it is quite unlikely that all of these stimuli directly bind to NLRP3.”
• The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “tetra-acylated lipid A, which is the reason why some bacteria, such as Francisella, can survive in the cytosol [121].”
• The Pathogenesis of Sepsis and Potential Therapeutic Targets (2019, background): “In the case of endogenous sepsis, liver cells are reported to release a large amount of HMGB-1, which binds to bacterial endotoxin (LPS); the bacterial endotoxin is transported to the cytoplasm through RAGE receptors expressed on vascular endothelial cells and macrophages, and this leads to cysteina”
• ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis) (2019, background): “The last decade has provided a wealth of information about the molecular details of the inflammasome and inflammatory caspase activation processes that promote pyroptosis and the release of the inflammatory cytokines interleukin (IL)-1 and IL-18; these findings are discussed in detail elsewhere (Kay”