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Cell. 2018 Nov 29;175(6):1651-1664.e14. doi: 10.1016/j.cell.2018.09.047. Epub 2018 Nov 1.

The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection.

Author information

1
Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: hhara@med.umich.edu.
2
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
3
Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan.
5
CIIL-Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019-UMR 8204, F-59000, Lille, France.
6
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
7
Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: gabriel.nunez@umich.edu.

Abstract

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.

KEYWORDS:

IL-18; Listeria monocytogenes; NLRP6; caspase-1; caspase-11; gram-positive bacteria; inflammasome; lipoteichoic acid

PMID:
30392956
PMCID:
PMC6294477
[Available on 2019-11-29]
DOI:
10.1016/j.cell.2018.09.047

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