The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release

J Immunol. 2011 Nov 15;187(10):5440-51. doi: 10.4049/jimmunol.1100790. Epub 2011 Oct 14.

Abstract

Streptococcus pneumoniae meningitis causes brain damage through inflammation-related pathways whose identity and mechanisms of action are yet unclear. We previously identified caspase-1, which activates precursor IL-1 type cytokines, as a central mediator of inflammation in pneumococcal meningitis. In this study, we demonstrate that lack of the inflammasome components ASC or NLRP3 that are centrally involved in caspase-1 activation decreases scores of clinical and histological disease severity as well as brain inflammation in murine pneumococcal meningitis. Using specific inhibitors (anakinra and rIL-18-binding protein), we further show that ASC- and NLRP3-dependent pathologic alterations are solely related to secretion of both IL-1β and IL-18. Moreover, using differentiated human THP-1 cells, we demonstrate that the pneumococcal pore-forming toxin pneumolysin is a key inducer of IL-1β expression and inflammasome activation upon pneumococcal challenge. The latter depends on the release of ATP, lysosomal destabilization (but not disruption), and cathepsin B activation. The in vivo importance of this pathway is supported by our observation that the lack of pneumolysin and cathepsin B inhibition is associated with a better clinical course and less brain inflammation in murine pneumococcal meningitis. Collectively, our study indicates a central role of the NLRP3 inflammasome in the pathology of pneumococcal meningitis. Thus, interference with inflammasome activation might be a promising target for adjunctive therapy of this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / physiology*
  • Animals
  • Apoptosis Regulatory Proteins
  • Brain Injuries / enzymology
  • Brain Injuries / immunology*
  • Brain Injuries / pathology*
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Cathepsin B / metabolism*
  • Cell Line, Tumor
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics
  • Disease Models, Animal
  • Humans
  • Hydrogen-Ion Concentration
  • Lysosomes / enzymology*
  • Lysosomes / immunology
  • Lysosomes / metabolism
  • Meningitis, Pneumococcal / enzymology
  • Meningitis, Pneumococcal / immunology*
  • Meningitis, Pneumococcal / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Severity of Illness Index

Substances

  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Pycard protein, mouse
  • Adenosine Triphosphate
  • Cathepsin B
  • Ctsb protein, mouse