The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection
The activator and composition of the NLRP6 inflammasome remain poorly understood. We find that lipoteichoic acid (LTA), a molecule produced by Gram-positive bacteria, binds and activates NLRP6. In response to cytosolic LTA or infection with Listeria monocytogenes, NLRP6 recruited caspase-11 and casp...
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Veröffentlicht in: | Cell 2018-11, Vol.175 (6), p.1651-1664.e14 |
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Sprache: | eng |
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Zusammenfassung: | The activator and composition of the NLRP6 inflammasome remain poorly understood. We find that lipoteichoic acid (LTA), a molecule produced by Gram-positive bacteria, binds and activates NLRP6. In response to cytosolic LTA or infection with Listeria monocytogenes, NLRP6 recruited caspase-11 and caspase-1 via the adaptor ASC. NLRP6 activation by LTA induced processing of caspase-11, which promoted caspase-1 activation and interleukin-1β (IL-1β)/IL-18 maturation in macrophages. Nlrp6−/− and Casp11−/− mice were less susceptible to L. monocytogenes infection, which was associated with reduced pathogen loads and impaired IL-18 production. Administration of IL-18 to Nlrp6−/− or Casp11−/− mice restored the susceptibility of mutant mice to L. monocytogenes infection. These results reveal a previously unrecognized innate immunity pathway triggered by cytosolic LTA that is sensed by NLRP6 and exacerbates systemic Gram-positive pathogen infection via the production of IL-18.
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•LTA from Gram-positive bacteria binds and activates NLRP6•Listeria and cytosolic LTA induce caspase-11 processing via NLRP6 and ASC•Processed caspase-11 promotes caspase-1 activation and IL-18 secretion•NLRP6 and caspase-11 exacerbate Gram-positive pathogen infection in vivo
Lipoteichoic acid produced by Gram-positive bacteria is sensed by the NLRP6 inflammasome and leads to the processing of both caspase-1 and caspase-11, exacerbating infection. |
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ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2018.09.047 |