title: 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.
authors.affiliation: Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Hagar
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Powell
authors.forename: Youssef
authors.initials: Y
authors.lastname: Aachoui
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.forename: Edward A
authors.initials: EA
authors.lastname: Miao
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D020169:Caspases / Q000096:biosynthesis* / Q000235:genetics; D053471:Caspases, Initiator; D045142:Cross-Priming; D004789:Enzyme Activation; D005603:Francisella; D016905:Gram-Negative Bacterial Infections / Q000276:immunology; D008050:Lipid A / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000276:immunology; D012475:Salmonella; D012480:Salmonella Infections / Q000276:immunology; D012772:Shock, Septic / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C512299:Ipaf protein, mouse; D008050:Lipid A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D011070:Poly I-C
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