2. Academic Validation
  3. The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection

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

  • Cell. 2018 Nov 29;175(6):1651-1664.e14. doi: 10.1016/j.cell.2018.09.047.
Hideki Hara 1,  Sergey S Seregin 2,  Dahai Yang 3,  Koichi Fukase 4,  Mathias Chamaillard 5,  Emad S Alnemri 6,  Naohiro Inohara 3,  Grace Y Chen 2,  Gabriel Núñez 7
Affiliations

Affiliations

  • 1 Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
  • 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: [email protected].
PMID: 30392956 DOI: 10.1016/j.cell.2018.09.047
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.

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